Originally published online as doi:10.1189/jlb.1204697 on February 2, 2005
Published online before print February 2, 2005
(Journal of Leukocyte Biology. 2005;77:598-625.)
© 2005
by Society for Leukocyte Biology
Myeloperoxidase: friend and foe
Seymour J. Klebanoff1
Department of Medicine, University of Washington, Seattle
1 Correspondence: Department of Medicine, Box 357185, University of Washington School of Medicine, Seattle, WA 98195-7185. E-mail: seym{at}u.washington.edu
ABSTRACT
Neutrophilic polymorphonuclear leukocytes (neutrophils) are
highly specialized for their primary function, the phagocytosis
and destruction of microorganisms. When coated with opsonins
(generally complement and/or antibody), microorganisms bind
to specific receptors on the surface of the phagocyte and invagination
of the cell membrane occurs with the incorporation of the microorganism
into an intracellular phagosome. There follows a burst of oxygen
consumption, and much, if not all, of the extra oxygen consumed
is converted to highly reactive oxygen species. In addition,
the cytoplasmic granules discharge their contents into the phagosome,
and death of the ingested microorganism soon follows. Among
the antimicrobial systems formed in the phagosome is one consisting
of myeloperoxidase (MPO), released into the phagosome during
the degranulation process, hydrogen peroxide (H
2O
2), formed
by the respiratory burst and a halide, particularly chloride.
The initial product of the MPO-H
2O
2-chloride system is hypochlorous
acid, and subsequent formation of chlorine, chloramines, hydroxyl
radicals, singlet oxygen, and ozone has been proposed. These
same toxic agents can be released to the outside of the cell,
where they may attack normal tissue and thus contribute to the
pathogenesis of disease. This review will consider the potential
sources of H
2O
2 for the MPO-H
2O
2-halide system; the toxic products
of the MPO system; the evidence for MPO involvement in the microbicidal
activity of neutrophils; the involvement of MPO-independent
antimicrobial systems; and the role of the MPO system in tissue
injury. It is concluded that the MPO system plays an important
role in the microbicidal activity of phagocytes.
Key Words: neutrophil microbicidal activity • hypochlorous acid • hydrogen peroxide • myeloperoxidase-mediated antimicrobial system • MPO-independent antimicrobial systems • MPO deficiency
INTRODUCTION
I have had a love affair with myeloperoxidase (MPO) for over
40 years, with particular regard to its role in the microbicidal
activity of phagocytes. I would like to describe to you how
this affair began, indicate some of its pleasures and disappointments,
and consider some unanswered questions regarding the role of
this enzyme.
In February 1957, I began a post-doctoral fellowship at The Rockefeller University (New York, NY), working in the laboratory of Reginald Archibald. This was an endocrine laboratory, and my interest at that time was in the thyroid gland, specifically in the biosynthesis of the thyroid hormones and in their mechanism of action. Thyroid hormone synthesis involves the iodination of tyrosine residues of thyroglobulin to form mono- and diiodotyrosine, which then couple to form the thyronine derivative, thyroxine or triiodothyronine. Both of these steps in thyroid hormone synthesis are catalyzed by a thyroid peroxidase. In regard to mechanism of action, it was found that phenolic hormones, namely the thyroid hormones and estrogens, had a marked stimulatory effect on some, but not all, reactions catalyzed by peroxidase [1
, 2
]. Thus, the oxidation of epinephrine, uric acid, and ferrocytochrome C by peroxidase and hydrogen peroxide (H2O2) was strongly stimulated by the phenolic hormones, whereas the oxidation of guaiacol was not. The stimulatory activity of thyroxine and estradiol on peroxidatic reactions was lost on the blocking of the phenolic hydroxyl group of the hormones by the formation of the methyl ether, suggesting that the phenolic hormones acted as oxidation-reduction catalysts, first being oxidized by peroxidase and H2O2 to a form, probably the phenoxy radical, which was then reduced back to its original form by reaction with an electron donor, whose oxidation was thus accelerated (Fig. 1
). In the absence of an appropriate electron donor, the phenolic hormones were further oxidized and inactivated.
With the excitement of youth, the question was posed: can the
stimulation of peroxidases account in part for the mechanism
of action of these hormones? Early studies were with horseradish
peroxidase, and mammalian peroxidases were sought, whose function
might be stimulated by the phenolic hormones. A number of distinct
peroxidases exist in mammalian tissues, which differ in their
primary structure, in their heme prosthetic group, and to some
degree, in the reactions they catalyze but have in common the
ability to increase the rate of H
2O
2-dependent reactions many
orders of magnitude. Two mammalian peroxidases had, at that
time, been purified, lactoperoxidase (LPO) [
3
] and MPO [
4
],
although their function was unknown. Both peroxidases were isolated,
and it was found that reactions catalyzed by these peroxidases
also were strongly stimulated by phenolic hormones. Tyrosine
was iodinated by a beef thyroid preparation [
5
] as well as
by LPO and MPO, but a stimulation of this reaction by the phenolic
hormones was not observed. It was decided to concentrate on
MPO, to search for a function for this enzyme and if found,
to see whether this function could be influenced by the phenolic
hormones.
Agner [6
], who had prepared MPO in a highly purified form in the early 1940s, had reported its presence in neutrophils at concentrations no less than 1–2% of the dry weight of the cells, and others [7
] reported its presence at concentrations greater than 5%. Agner initially called the enzyme verdoperoxidase, as a result of its intense green color, but the name was subsequently changed to myeloperoxidase. It is what gives pus its green color. Cytochemical studies dating back to the early 1900s suggested the presence of a peroxidase in the cytoplasmic granules of mature granulocytes, and subsequent studies indicated its presence entirely in the azurophil (primary) granules of these cells. MPO synthesis is initiated in the promyelocyte stage of neutrophil development and terminates at the beginning of the myelocyte stage, at which time the MPO-containing azurophil granules are distributed to daughter cells, where they intermingle with the newly formed peroxidase-negative, specific (secondary) granules. The MPO-containing granules in the mature human neutrophil are heterogeneous by density [8
] and by morphology [9
]. Human monocytes also contain MPO-positive granules, although they are fewer in number than in neutrophils [10
]. The MPO-containing granules are formed in bone marrow promonocytes, are readily apparent in mature monocytes, and are generally lost when monocytes mature into macrophages in tissues (see Atherosclerosis and Multiple sclerosis below for evidence for the presence of MPO in tissue macrophages under certain conditions). A peroxidase is also present in the cytoplasmic granules of eosinophils [11
]; however, it differs from MPO structurally and in its function [12
].
MPO is the product of a single gene, which has been cloned in a number of laboratories [13
14
15
16
17
18
19
]. The gene is 
11 kb in size, composed of 11 introns and 12 exons [20
], and located in the long arm of chromosome 17 in segment q12–24 [17
, 21
22
23
]. Its initial translation product is an 80-kD protein [24
], which following proteolytic removal of the 41 amino acid signal peptide, undergoes N-linked glycosylation with the incorporation of mannose-rich side-chains [25
, 26
] to generate an 89- to 90-kD enzymatically inactive apoproMPO [20
], which forms a complex in the endoplasmic reticulum with the calcium-binding proteins calreticulin and calnexin, which act as molecular chaperones [27
, 28
]. With the insertion of a heme, apoproMPO is converted to the enzymatically active proMPO [29
30
31
]. The removal of the N-terminal 125 amino acid pro-region by proteolytic cleavage results in the production of a 72- to 75-kD protein, which undergoes a second proteolytic cleavage to generate the 467 amino acid heavy (
) subunit (57 kD) and the 112 amino acid light (ß) subunit (12 kD) of MPO, which associate as a heavy-light protomer. Mature MPO has a molecular mass of 150 kD and consists of a pair of heavy-light protomers [32
33
34
34
] whose heavy subunits are linked by a disulfide bond along their long axis [32
]. The mannose-rich carbohydrate and the two hemes are covalently bound to the heavy subunit [33
34
35
]. Reduction and alkylation result in the cleavage of MPO into hemi-MPO, which consists of a single and ß protomer. It retains enzymatic and bactericidal activity [32
, 36
]. The two heavy () subunits appear to be structurally different [37
, 38
]. The X-ray crystallographic structure of canine [39
40
41
42
] and human [43
] MPO has been described.
In 1920, Graham [44
] first reported the release of peroxidase from neutrophil cytoplasmic granules during phagocytosis as follows: "Very marked changes in the granules may readily be determined by the study of leucocytes engaged in phagocytosis, as for example, in opsonic preparations or in smears of pus. Smears from an active case of gonorrhoea are very satisfactory. When such preparations are stained with a ‘peroxidase’ reagent, interesting examples of the more or less complete disappearance of the granules from the individual cells may be obtained. While exceptions may occur, it may be stated in general that the granules disappear from the leucocytes progressively as the number of bacterial inclusions in the cell increases." In 1960, Hirsch and Cohn [45
] described in detail the degranulation process in phagocytes, in which the membrane of the cytoplasmic granules fused with that of the developing phagosome, the common membrane then ruptured, and the contents of the granules were discharged with great force into the phagosome. Cohn and Hirsch [46
] then isolated the granules of rabbit granulocytes and demonstrated the presence in them of a variety of hydrolases as well as an antimicrobial protein, which in 1956, Skarnes and Watson [47
] had called leukin, and Hirsch [48
] had called phagocytin. The concept that granule components released into the phagosome may be toxic to ingested organisms was thus born. Subsequent studies by myself [49
] and others indicated that MPO was among the granule enzymes discharged into the phagosome during the degranulation process. MPO also can be released to the outside of the cell by leakage before complete closure of the developing phagosome or in response to stimulation by an antibody/complement-coated surface too large to be ingested. MPO is a strongly basic protein with an isoelectric point >10 [6
] and thus binds avidly to negatively charged surfaces. It can be seen coating ingested microorganisms and when released to the outside of the cell, to biological membranes. MPO, when released, can be inactivated by products of the respiratory burst [50
, 51
] or be cleared from the extracellular fluid by uptake by macrophages [52
, 53
] through reaction with the mannose receptor [53
]. Further, the uptake of microorganisms coated with extracellularly released MPO [54
] or eosinophil peroxidase [55
56
57
] may arm the macrophages, resulting in an associated increased destruction of the ingested organisms.
It was clear at that time (1959–60) that the process of phagocytosis and degranulation by phagocytes was associated with increased metabolic activity [58
, 59
]. Of particular interest was the burst of oxygen consumption, which was first reported by Baldridge and Gerard [60
] in 1933. However, it was not until 1961, when Iyer, Islam, and Quastel [61
] reported that the respiratory burst of phagocytes was associated with the formation of H2O2, that a product of the respiratory burst was implicated in antimicrobial activity. They stated, "In the consideration of the various factors that may operate in bringing about bactericidal action during phagocytosis, the possibility that hydrogen peroxide is formed during this process must be taken into account. It is unlikely that hydrogen peroxide is wholly responsible for the non-specific bactericidal effects of phagocytosis, but it will surely be one of the responsible agents."
As the primary function of neutrophils is the phagocytosis and destruction of microorganisms, the question was posed: Is the function of MPO in neutrophils the destruction of ingested microorganisms? With a vial of green MPO in hand, I proposed to Jim Hirsch that we look at the antimicrobial properties of this enzyme. Our first studies in this regard in 1961–62 were disappointing. We mixed viable microorganisms with MPO and sublethal levels of H2O2 and found no fall in the viable cell count. It was theoretically possible that MPO, rather than being directly toxic to bacteria in the presence (or absence) of H2O2, could act indirectly by catalyzing the conversion of a nontoxic agent to a toxic one. Thus, Kojima [62
] reported that peroxidase (source unspecified) and H2O2 can increase the germicidal effect of a number of phenols by conversion to the corresponding quinone. Iodide seemed ideal for this purpose, as it is nontoxic but is oxidized by peroxidase and H2O2 to iodine, a well-known germicidal agent. When iodide was added to the MPO-H2O2 system, the solution turned yellow as iodine was formed, and the microorganisms were killed. The concentration of iodide required, however, was considerably greater than physiologic. At this point, I moved from The Rockefeller University to the University of Washington (Seattle), and this line of study was put to one side.
My interest in the antimicrobial properties of peroxidases resurfaced a few years later in saliva. In 1934, an antilactobacillus system was described in saliva, which differed from the then-known antimicrobial systems. Its nature remained a mystery until 1959 when Zeldow reported [63
] that this system could be divided into a heat-stable, dialyzable component and a heat-labile, nondialyzable component, each of which was ineffective alone but which when combined, was toxic to the lactobacilli. In 1962, Dogon, Kerr, and Amdur [64
] reported that the heat-stable, dialyzable component was the thiocyanate ion, and in 1965, Luebke and I reported [65
] that the heat-labile, nondialyzable component was the salivary peroxidase (LPO). H2O2 was an additional requirement for this system [65
, 66
]. It was fortuitous that lactobacillus was the target organism used in the early studies, as this organism can generate H2O2 in large amounts and thus, was able to generate the H2O2 required for its own destruction when combined with LPO and thiocyanate ions. When H2O2 or a H2O2-generating system was added, toxicity was extended to microorganisms which did not generate H2O2 themselves. A similar antimicrobial system was detected in milk [67
].
The observation at that time that MPO could replace LPO in the peroxidase-thiocyanate-H2O2 antimicrobial system [65
, 66
] renewed interest in the possibility that MPO served an antimicrobial function in the neutrophil. In 1967, I reported that MPO, H2O2, and iodide, bromide, chloride, or thiocyanate ions formed a powerful antimicrobial system in neutrophils [68
69
70
] (Fig. 2
). Of particular interest was the observation that chloride, at physiologic concentrations, could meet the halide requirement of the MPO-dependent antimicrobial system, although it was ineffective in the LPO-H2O2 system. In 1967, McRipley and Sbarra [72
] reported that a guinea pig leukocyte extract was bactericidal when combined with H2O2, and they subsequently confirmed the requirement for a halide [73
].
MECHANISMS OF H2O2 FORMATION FOR THE MPO SYSTEM
The H
2O
2 required for the MPO-mediated antimicrobial system
may come from a variety of sources.
Phagocyte NADPH oxidase
Rossi and Zatti [74
] first proposed in 1964 that a NADPH oxidase was responsible for the respiratory burst of phagocytes. In 1973, Babior, Kipnes, and Curnutte [75
] reported that the initial product of the respiratory burst oxidase was the O
as follows:
and there followed 30 years of effort worldwide
designed to elucidate the nature of the O
-generating NADPH oxidase
system of phagocytes (for review, see refs. [
76
77
78
79
]).
A major advance was the demonstration that the NADPH oxidase
could be activated in cell-free leukocyte preparations by an
anionic detergent such as arachidonic acid, sodium dodecyl sulfate,
or other cis-unsaturated fatty acids [
80
81
82
]. The NADPH
oxidase activated in this way could be separated by centrifugation
into a particulate (membrane) fraction and a soluble (cytosolic)
fraction, both of which were required for NADPH oxidase activity.
In 1978, Segal and Jones [
83
] reported the presence of a novel
b-cytochrome in high concentrations in normal neutrophils as
well as in monocytes, macrophages, and cosinophils [
84
]. It
is a heterodimer consisting of a 91-kD glycoprotein (ß
subunit), designated gp91
phox, and a 22-kD polypeptide (
subunit),
designated p22
phox. The b-cytochrome has a characteristic absorption
peak at 558 nm and a low mid-point potential (–245 mV),
which allows it, by oxidation-reduction, to directly reduce
O
2 to O
. The b-cytochrome also contains a flavin (flavin adenine
dinucleotide) as part of the electron transport chain and thus,
has been termed flavocytochrome b
558. The gene for the heavy
subunit of the b-cytochrome (gp91
phox) was first identified
and cloned by Orkin and his colleagues [
85
,
86
] by "reverse
genetics" in which the gene was initially located on the X chromosome
by linkage analysis and its protein product subsequently determined
from the base sequence. In the resting cell, the b cytochrome
is present largely in the membranes of secondary (specific)
granules and secretory vesicles in the cytoplasm and is transported
to the cell (or phagosomal) membrane when the leukocyte is stimulated.
It is the particulate (membrane) component of the cell-free
NADPH oxidase system. The soluble (cytoplasmic) components of
the oxidase consist of 67 kD, 47 kD, and 40 kD proteins, designated
p67
phox, p47
phox, and p40
phox and the low molecular weight guanosine
5'-triphosphate (GTP)-binding protein rac 1 [
87
] or rac 2 [
88
].
Rac 2, which is a member of the Rho family of small GTPases,
appears to be the predominant GTP-binding protein of human neutrophils
[
89
]. The development of a polyclonal antiserum, which recognized
p47
phox and p67
phox [
90
], led to the cloning and structural
characterization of the cytoplasmic components of the oxidase
[
91
,
92
]. The NADPH oxidase is activated by the migration
of the cytoplasmic components to the cell membrane to form a
complex with the membrane component flavocytochrome b
558. This
is facilitated by the phosphorylation, largely by protein kinase
C, of p47
phox, which binds to the 22-kD
subunit of the b-cytochrome.
The dissociation of Rac from a cytoplasmic complex with an inhibitor
molecule (guanosine diphosphate dissociation inhibitor) occurs,
with the conversion of Rac from its guanosine 5'-diphosphate-bound
inactive form to its GTP-bound active form (for a review of
NADPH oxidase regulation by Rac, see ref. [
93
]). The activated
NADPH oxidase transports electrons from NADPH on the cytoplasmic
side of the membrane to oxygen in the extracellular fluid or
when the membrane is invaginated in the intraphagosomal space
to form O
. The NADPH-binding site, flavin and heme, required
for this electron transport, appears to be present in the gp91
phox component of the NADPH oxidase, with the cytosolic components
serving an activating function.
In 1967 Quie et al. [94
] described a microbicidal defect in the neutrophils of patients with chronic granulomatous disease (CGD) of childhood, a condition that had been described clinically 10 years earlier by Berendes, Bridges, and Good [95
]. CGD is characterized by severe, repeated, and widespread infections, generally involving staphylococci, certain Gram-negative bacteria, and fungi and affecting a variety of tissues. Infections generally appear in infancy and often result in early death. The lesions are often characterized by granulomata with characteristic lipid-filled histiocytes and thus the name chronic granulomatous disease. In 1967, Holmes, Page, and Good [96
] reported that the neutrophil microbicidal defect in CGD was associated with the absence of respiratory burst activity, suggesting an important role for the respiratory burst in the microbial activity of phagocytes. The basis for the respiratory burst defect in CGD is mutations in components of the NADPH oxidase, namely gp9lphox, p47phox, p67phox, and p22phox (for review, see refs. [78
, 79
, 97
, 98
]). The gp91phox gene is located on the X-chromosome, and thus, CGD due to mutations in that gene (60% of cases), affects males and is generally [99
] but not always [100
] associated with the absence of flavocytochrome b558. The remaining cases of CGD are autosomal in nature and occur with equal frequency in males and females. Approximately 30% of patients with CGD have a mutation in p47phox, 5% in p67phox, and 5% in p22phox [90
, 97
, 98
, 101
]. Recently, an infant with decreased Rac2 levels (41% of normal in neutrophil lysate, 31% of normal in neutrophil cytosol), a dominant-negative Rac2 mutation, multiple neutrophil functional abnormalities, and delayed wound-healing, complicated by infection, has been described [102
103
104
].
The initial product of the respiratory burst oxidase, O, exists in equilibrium with its protonated form, the perhydroxyl radical (HO2·) The pKa of the dissociation is 4.8 so that the radical exists almost entirely as O at neutral or alkaline pH. O reacts predominantly as a reductant, where it gives up an electron and is converted back to oxygen. It can, however, also act as an oxidant, where it accepts an electron and is converted to H2O2. When two molecules interact, one is oxidized, and the other is reduced in a dismutation reaction with the formation of O2 and H2O2. This reaction can occur spontaneously or be catalyzed by superoxide dismutase (SOD). Spontaneous dismutation occurs optimally at pH 4.8, where O and HO2· are present in equal concentrations. At this pH, the rate constant for spontaneous dismutation approaches that of SOD-catalyzed dismutation. As the pH rises, and O predominates, the rate of spontaneous dismutation falls sharply, and catalysis by SOD becomes more significant. There is no evidence that leukocytic SOD is released into the phagosome; SOD, however, can be introduced there as a component of the ingested organism.
Vascular NAD(P)H oxidase
A NAD(P)H oxidase, similar but not identical to the leukocyte enzyme, is present in vascular cells [105
106
107
108
109
110
] and may serve as a source of reactive oxygen species (ROS) in or adjacent to the vessel wall. It is of interest in this regard that in a rodent model of acute inflammation in which rats are treated with lipopolysaccharide, MPO, presumably released by stimulated phagocytes in the bloodstream, can be detected on the endothelial surface, within the endothelial cells, and in the subendothelial space, where it may react with H2O2 formed by the vascular NAD(P)H oxidase to modulate nitric oxide (NO·)-dependent signaling [111
].
NOX/DUOX enzymes
The NADPH oxidase of phagocytes is the most reactive of a family of oxidases designated NOX for NADPH oxidase or DUOX for dual oxidase [112
, 113
], which contain a region with homology to the gp91phox of the phagocyte NADPH oxidase. The DUOX enzymes also contained a peroxidase domain. A NOX homologous to the phagocyte gp91phox was first described in colon epithelial cells by Lambeth and his colleagues in 1999 [114
] and was designated MOX1 (currently NOX1). In subsequent studies, this group and others [115
116
117
118
119
] have identified NOX1 as well as homologues, designated NOX3, NOX4, and NOX5, in a variety of other tissues [113
]. The phagocyte NADPH oxidase was designated NOX2. In general, ROS production by the nonphagocyte NOX enzymes is considerably less than that produced by the phagocyte NOX (NOX2). However, recently, the proteins NOX organizer 1 and NOX activator 1, with homology to the NOX2 p47phox and p67phox, respectively, have been cloned from colon epithelial cells [120
121
122
123
], and their inclusion with NOX1 greatly increases ROS production. Elevated calcium levels can also increase superoxide production by some NOX enzymes, e.g., NOX5, which contains four EF-hands [118
, 124
].
DUOX1 and 2 were first described in the thyroid gland [116
, 117
, 125
, 126
] and were designated THOX1 and -2 [117
]. The THOX proteins are colocalized with the thyroid peroxidase at the apical membrane of human thyroid cells [125
], and these two enzymes thus may combine to catalyze thyroid hormone synthesis. The DUOX (THOX) enzymes by virtue of having a superoxide-generating and a peroxidase center also may serve to generate and use H2O2 for thyroid hormone synthesis, although it is not clear that the DUOX enzymes have appreciable peroxidase activity. Mutations in DUOX2 (THOX2) are associated with a loss of thyroid hormone synthesis and can lead to congenital hypothyroidism [126
]. The DUOX1 of Caenorhabditis elegans uses its dual functionality to facilitate cuticle formation by cross-linking of tyrosine residues in extracellular proteins [121
]. DUOX1 and DUOX2 were found in salivary gland, rectum, trachea, and bronchium, and it was proposed that these enzymes serve as the source of H2O2 for a LPO-mediated antimicrobial system at mucosal surfaces [127
].
Soluble H2O2-generating enzymes
Certain soluble enzyme systems can form H2O2, some via a O intermediate and others, without the formation of detectable O. Thus, xanthine oxidase and amine oxidase form O and H2O2, whereas glucose oxidase forms H2O2 without an apparent O intermediate. Xanthine oxidase has been implicated as a source of ROS in ischemia-reperfusion injury [128
].
Mitochondrial metabolism
Mitochondrial electron transport systems in a variety of cell types generate small amounts of O and H2O2; however, it is not clear whether the H2O2 formed in this way can be released to the outside of the cell in sufficient amounts to be damaging to adjacent tissue.
Microbial metabolism
Certain microorganisms, namely those designated as lactic acid bacteria, generate H2O2 [129
]. These microorganisms, which include strains of streptococci, pneumococci, and lactobacilli, lack heme and thus do not use the cytochrome system (which converts oxygen to water) for terminal oxidations. Rather, flavoproteins are used, which convert oxygen to H2O2. These organisms also lack a heme catalase and thus do not efficiently degrade H2O2, which accumulates in the medium. The finding that lactobacilli can serve as a source of H2O2 for the peroxidase-mediated antimicrobial system is pertinent to the female genital tract, as the predominant organism in the normal human vagina is the lactobacillus. In one study [130
], 96% of normal women harbored H2O2-generating lactobacilli, whereas 4% harbored lactobacilli, which did not generate H2O2. Bacterial vaginosis typically occurs in sexually active women who complain of vaginal discharge, irritation, and odor. There is an associated overgrowth with Gram-negative coccobacilli, Gardnerella vaginalis, and certain anaerobes in the vagina associated with a decrease in H2O2-generating lactobacilli. In our series, only 6% of women with bacterial vaginosis harbored H2O2-producing lactobacilli, and 36% harbored lactobacilli which did not generate H2O2 [130
]. Similarly, the absence of H2O2-generating lactobacilli predisposes women to vaginal Escherichia coli colonization and urinary tract infection [131
]. H2O2-producing lactobacilli, particularly in the presence of peroxidase and a halide, are bactericidal to G. vaginalis [132
] and E. coli [133
] and are viricidal to human immunodeficiency virus type 1 (HIV-l) [134
]. Lactobacilli alone at low concentrations also are toxic to certain anaerobes through the formation of H2O2 [132
]. Peroxidase activity has been detected in vaginal fluid specimens from most women in amounts sufficient to induce a microbicidal effect in vitro [132
], and chloride is also present in human cervical mucus in excess [135
]. These findings raise the possibility that production of H2O2 by lactobacilli may represent a nonspecific host defense mechanism in the normal vagina in the presence or absence of peroxidase of leukocytic or uterine origin.
Nonoxynol-9 is a nonionic detergent with spermicidal activity that is widely used as the active ingredient in a number of vaginal contraceptive preparations. In addition, nonoxynol-9 is toxic to a variety of microorganisms, suggesting that nonoxynol-9-containing contraceptive preparations also may provide protection against certain genital infections. Epidemiological studies have provided support for this protective effect [136
]. Paradoxically, women who use spermicides have increased vaginal colonization with E. coli [131
, 137
] and an increased incidence of bacteriuria with this organism. E. coli are resistant to the direct toxic effect of nonoxynol-9 [138
], whereas lactobacilli are highly sensitive. This raises the possibility that suppression of the growth of lactobacilli in the vagina by nonoxynol-9 may favor the survival of E. coli by preventing its destruction by lactobacilli-derived H2O2 in the presence or absence of peroxidase and a halide. Nonionic detergents including nonoxynol-9 form peroxides when exposed to oxygen for a prolonged period, and the peroxides so formed can be toxic to E. coli when combined with MPO and chloride [133
].
PRODUCTS OF THE MPO-MEDIATED ANTIMICROBIAL SYSTEM
It is the prevailing view that the initial product formed by
the oxidation of chloride by MPO and H
2O
2 is HOCl [
139
140
141
].
MPO forms three different complexes on reaction with products
of the respiratory burst of phagocytes, compounds I, II, and
III (
Fig. 3
), with distinct spectral properties. H
2O
2 at stoichiometric
concentrations [
142
] (or more efficiently, at a 20-fold excess
of H
2O
2 [
143
]), reacts rapidly with the iron of MPO (which
is normally in the ferric form) to form a complex compound I
[
142
], which has an oxygen bound by a double bond to the heme
iron. Compound I can also be formed by the reaction of MPO with
HOCl [
144
]. Compound I, the primary catalytic complex of MPO,
reacts with a halide in a two-electron reduction to form the
corresponding hypohalous acid and regenerating the native Fe
3+-MPO.
The reaction of compound I with excess H
2O
2 results in the formation
of compound II, which is inactive with respect to the oxidation
of chloride [
145
]. Compound II can be reduced to the active,
native enzyme by O
[
146
147
148
], as well as by a number of
other reducing agents [
146
,
149
,
150
] with restoration of
the ability to oxidize chloride to form HOCl. Kettle and Winterbourn
[
146
,
148
,
151
] have proposed that one of the functions of
O
may be to maintain MPO in an active form in the presence of
excess H
2O
2. O
may thus potentiate oxidant damage at inflammatory
sites by optimizing the MPO-dependent production of HOCl, and
the anti-inflammatory effect of SOD may be in part a result
of the inhibition of this reaction. However, the conversion
of compound II to native MPO by O
is considerably slower than
the comparable conversion by certain other reducing agents,
e.g., ascorbic acid [
143
,
152
], raising a question about the
physiologic role of the O
-dependent activation of MPO compound
II. O
can also react directly with native MPO to form compound
III [
142
,
153
154
155
156
], an oxyperoxidase, which like oxyhemoglobin,
has oxygen attached to the heme iron [
157
,
158
]. Compound
III is unstable, decaying to native MPO with a half-decay time
of several minutes at room temperature [
157
,
159
]. Compound
III also can be converted to the native enzyme by reducing agents
such as ascorbic acid with the return of compound I-dependent
HOCl production [
152
]. Compound III, which has been detected
in intact, stimulated neutrophils [
154
], can react with a number
of compounds, both electron donors [
157
,
160
161
162
] and
electron acceptors [
162
], raising the possibility that it is
a catalytically active form of MPO in neutrophils. The reaction
of MPO with O
to form compound III, however, is an order of
magnitude slower than the reaction of native MPO with H
2O
2 [
156
].
As HOCl has a p
Ka of 7.53, it exists as a mixture of the undissociated
acid and the hypochlorite ion at physiologic pH levels (
Fig. 4
). When the pH is lowered, as may occur in the phagosome,
HOCl predominates, and it can react with excess chloride to
form molecular chlorine (Cl
2) [
163
164
165
]. These products,
which are the reactive components of standard household bleach,
are highly reactive and thus, short-lived, oxidizing agents
that can attack the microorganisms at a variety of chemical
sites [
166
]. Essentially, any oxidizable group on the organism,
e.g., sulfhydryl groups, iron-sulfur centers, sulfur-ether groups,
heme groups, unsaturated fatty acids, can be oxidized, and as
a consequence, there may be a loss of microbial membrane transport
[
167
], an interruption of the membrane electron transport chain
[
168
], dissipation of adenylate energy reserves [
169
], and
suppression of DNA synthesis with associated disruption of the
interaction of the microbial cell membrane with the chromosomal
origin of replication [
170
]. In addition, HOCl reacts with
nitrogen-containing compounds to form nitrogen-chlorine derivatives
such as monochloramines and dichloramines, which can degrade
to the corresponding aldehyde [
171
,
172
]. Some of these compounds
retain oxidizing activity. Taurine, which is present at a high
concentration in neutrophil cytoplasm [
173
,
174
], reacts with
HOCl to form taurine chloramine, which is less toxic than HOCl,
and this reaction has thus been implicated as a mechanism by
which neutrophils are protected from HOCl released into the
cytoplasm. Taurine chloramine, however, retains some biologic
activity [
175
], as does histamine chloramine [
176
]. The chloramines
are long-lived, thus providing a mechanism for the prolongation
of the oxidant activity of the peroxidase system and for the
penetration of MPO-derived oxidants into complex biological
fluids to be toxic at a distance under conditions in which the
more reactive products are readily scavenged. Tyrosine or tyrosine
residues of protein also can be chlorinated to form 3-chlorotyrosine
or 3,5-dichlorotyrosine [
163
,
177
]. Although it is not known
whether tyrosine chlorination is itself damaging to microorganisms
or tissues, it serves as a specific marker of MPO activity (see
ref. [
166
]). MPO and H
2O
2 also can oxidize tyrosine directly,
i.e., in the absence of chloride, to form the tyrosyl radical,
which can cross-link to form free and protein-dityrosine linkages
[
178
179
180
181
] or react with superoxide to form tyrosine
peroxide [
182
].
Hydroxyl radical (·OH)
In 1894, Fenton [
183
] described the strong oxidizing activity
of a mixture of ferrous sulfate and H
2O
2, and in 1934, Haber
and Weiss [
184
] reported that ·OH was the powerful oxidant
formed as follows:
When the free iron
concentration is limiting, as is the case in biological fluids,
the reduction of the ferric iron formed is required for the
complete conversion of H
2O
2 to ·OH. This can be accomplished
by O
as follows:
with the overall reaction
being the iron-catalyzed interaction of H
2O
2 and O
to form ·OH
(Haber-Weiss reaction, superoxide-driven Fenton reaction) as
follows:
As H
2O
2 and O
are formed by
stimulated phagocytes, their interaction to form ·OH
might be expected. Trace metal (e.g., Fe) catalysis of the Haber-Weiss
reaction is required, as H
2O
2 and O
do not interact directly
at an appreciable rate. The free iron concentration in biological
fluids is extremely low and would be expected to limit the formation
of ·OH by the Haber-Weiss reaction. The bulk of the body’s
iron is bound to protein for storage and transport or to form
a catalytic center. The ability of protein-bound iron to catalyze
the Haber-Weiss reaction under physiological conditions has
not been clearly demonstrated.
·OH appear to be formed by the MPO-H2O2-Cl– system in neutrophils, at least in small amounts (for review, see ref. [12
]). One of the methods for the detection of highly labile free radicals is to form a relatively stable radical adduct with a spin trap, which can be detected by electron spin resonance spectroscopy. A new spin trap procedure for the detection of ·OH, in which ·OH reacts with ethanol to form the -hydroxyethyl radical, which forms a measurable adduct with the spin trap -(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN), was applied by Ramos et al. [185
] to neutrophils. This procedure was an order of magnitude more sensitive than previously used methods, and with it, ·OH formation by stimulated neutrophils could be detected. Further, evidence was presented suggesting that the formation of ·OH by stimulated neutrophils was by a MPO-dependent mechanism. They proposed that MPO catalyses the H2O2-dependent formation of HOCl, which reacts with O to form ·OH as follows:
 |
 |
The evidence was as follows: ·OH formation
was inhibited by SOD implicating O
, by catalase implicating
H
2O
2, and by azide implicating MPO. Further, the reaction of
purified MPO with the xanthine oxidase system, which generates
O
and H
2O
2 , resulted in the formation of ·OH in a reaction
that was dependent on chloride and was inhibited by SOD, catalase,
and azide. However, less than 1% of neutrophil O
and H
2O
2 production
could be accounted for by the formation of ·OH by this
mechanism, raising a question about its physiological significance.
·OH is an extremely reactive radical, which will react
with essentially the first molecule it meets. Thus, it would
need to be formed in the immediate vicinity of the crucial target
on the bacterial surface [
186
]. The HCO
3· radical, formed
by the reaction of ·OH with CO
2, may be an effective
microbicide under the conditions present in the phagosome [
186
].
Singlet oxygen (1O2)
In early studies, formation of 1O2 by neutrophils could not be detected using the conversion of cholesterol to 3ß-hydroxy-5-cholest-6-ene-5-hydroperoxide as a specific marker of 1O2 formation [187
, 188
] or by the use of instrumentation, which could detect the emission of delta 1O2 decay at 1270 nm [189
, 190
], leading to the suggestion that 1O2 is, at best, a minor product of the respiratory burst. However, Steinbeck et al. [191
] have provided evidence supporting the formation of 1O2 by the MPO system in neutrophils, using the conversion of 9,10 diphenylanthracene (DPA) to the DPA-endoperoxide as a specific and sensitive measure of 1O2 formation. When neutrophils ingested beads coated with DPA, up to 19% of the oxygen consumed could be accounted for by the formation of 1O2. 1O2 was also detected with this technique as a product of the MPO-H2O2-chloride system, and the mechanism for its formation was the reaction of H2O2 with HOCl/OC1– (or Cl2), a classical mechanism for the formation of 1O2 as follows:
 |
 |
Arisawa et al. [
192
], using a chemiluminescence
method for the detection of
1O
2, reported the formation of
1O
2 by the MPO-H
2O
2-chloride system, which peaked at pH 7. Further,
using a highly sensitive detection system for light emission
at 1270 nm, Kiryu et al. [
193
] detected
1O
2 formation by the
MPO-H
2O
2-chloride system under physiological conditions, i.e.,
at pH 7.4 and without the use of deuterium oxide. However, the
formation of
1O
2, in appreciable amounts by stimulated phagocytes,
remains in question.
Ozone (O3)
Recently, it has been proposed that antibodies, regardless of antigen specificity, can catalyze the oxidation of water by 1O2 to produce H2O2 and O3 [194
195
196
197
]. O3 has also been proposed as a product of the respiratory burst of neutrophils, using 1O2 formed by the MPO system for its formation [198
]. O3 is bactericidal, and a combination of H2O2 and O3 is more toxic to microorganisms than either alone. This thus may be an additional mechanism for the destruction of microorganisms by the MPO system of phagocytes.
The formation of O3 by stimulated phagocytes was based largely on the conversion of indigo carmine to isatic sulfonic acid, a reaction that can be induced by O3. However, O is also capable of this reaction, and the involvement of O in the conversion of indigo carmine to isatic sulfonic acid by stimulated phagocytes is suggested by the inhibitory effect of SOD and the absence of inhibition by catalase, azide, and methionine [199
].
EVIDENCE FOR MPO INVOLVEMENT IN NEUTROPHIL MICROBICIDAL ACTIVITY
A number of lines of evidence support an important role for
MPO in the microbicidal activity of neutrophils (for reviews,
see refs. [
12
,
200
,
201
]).
MPO, H2O2, and a halide form a powerful antimicrobial system
Initial studies indicated that the halide requirement could be met by iodide, bromide, or chloride [68
69
70
] or by the pseudohalide, thiocyanate [65
, 66
]. More recently, nitrite was shown to substitute for the halide in the MPO-mediated antimicrobial system in vitro [202
, 203
]. Nitrite was bactericidal at concentrations down to 10–3M when combined with MPO and a source of H2O2 [202
]. Nitrite can be formed in phagocytes as a product of the metabolism of NO·; however, it is not clear that nitrite is formed in sufficient amounts to contribute significantly to the microbicidal activity of the MPO system.
It is the prevailing view that chloride is the physiological halide, as it is present in biological fluids at concentrations considerably higher than that required. Iodide is the most effective halide on a molar basis; however, the concentration of free iodide in biological fluids is very low (<1 mg%). The iodinated hormone, thyroxine, can substitute for iodide in the cell-free MPO system [69
], presumably, at least in part, as a result of its deiodination by the peroxidase system [204
, 205
]. Bromide is intermediate between iodide and chloride in effectiveness and concentration; however, at levels present in plasma, chloride is preferentially used by the MPO system [206
]. The presence of brominated compounds (e.g., 3-bromotyrosine) as well as chlorinated compounds (e.g., 3-chlorotyrosine) in the peritoneal fluid of wild-type mice with sepsis at concentrations considerably higher than those seen in peritoneal fluid of septic MPO-deficient mice supports a contribution by bromide to the MPO-mediated antimicrobial system in vivo [207
]. Thiocyanate is readily oxidized by MPO and H2O2 [208
, 209
] even in the presence of physiologic concentrations of chloride [208
], suggesting that the product of thiocyanate oxidation, hypothiocyanous acid, may contribute to the antimicrobial activity of the MPO system.
MPO and H2O2 are formed or released by neutrophils at a time and place appropriate to the microbicidal act
MPO [49
] and H2O2 [210
, 211
] can be detected in the phagosome by electronmicroscopic cytochemical techniques. The oxidase responsible for O [212
] and H2O2 [211
] production was detected in low amounts on the plasma membrane of resting neutrophils and following phagocytosis, was found in considerably increased amounts in the phagosome. These findings indicate that the oxidase is membrane-associated and is internalized and activated during phagocytosis with the generation of H2O2 within the phagosome.
The formation of HOCl accounts for a high proportion of the oxygen consumed in the respiratory burst
Values of at least 28% [213
] and 72% [214
] with different stimuli have been proposed. Similarly, in one study, 40% of the H2O2 generated by zymosan-stimulated neutrophils was used for the formation of HOCl [215
]. These are minimum values, as they do not take into account the presence of proteins and other scavengers that compete for HOCl in the assay system [213
]. Jiang et al. [216
] concluded from their studies that "the neutrophil is capable of intraphagosomal generation of HOCl in sufficient quantities to kill entrapped bacteria on a time scale that is associated with bacterial death", and Hampton et al. [200
] concluded from their studies that "enough HOCl is generated in the phagosome for it to be responsible for killing."
MPO, H2O2, and a halide interact in the phagosome adjacent to the ingested organism
The production of ROS and their reactions occur in the microenvironment of the phagosome, which is complex and constantly changing [186
]. Initially, when opsonized bacteria are ingested by phagocytes, microbe-associated ligands, generally antibody and/or complement, bind to membrane receptors in a continuous and circumferential manner, as the cell membrane invaginates to form a tight phagosome, with little or no space between the microbe and phagosome membrane (zipper phenomenon [217
]). This process is associated with the activation of the NADPH oxidase and with degranulation, which releases ROS and the granule components, including MPO, into the phagosome. The latter process creates a space between the microbe and the membrane of the phagosome, which contains a variety of granule components through which the secreted ROS would need to travel to reach the ingested microbe. Some ROS, e.g., ·OH, are highly reactive and would be expected to be scavenged quickly prior to reaching the microbe. Other ROS, e.g., H2O2, are less reactive and thus have longer diffusion distances. That H2O2 can reach the microbe and react with it is suggested by the OxyR-mediated transcriptional response in E. coli, which is elicited by reagent H2O2 and when complement-opsonized E. coli are ingested by intact phagocytes. This suggests that H2O2 formed in the phagosome can reach the microbe at concentrations adequate to initiate an OxyR response [218
]. MPO, being present in human neutrophils at concentrations no less than 1–2% of the dry weight of the cells [6
], would be expected to be present in the phagosome in very high concentrations. Being a highly cationic protein with an isoelectric point greater than 10 [6
], it can bind to the negatively charged surface of the microorganism and react there with H2O2 to initiate MPO-dependent oxidant formation in close proximity to the ingested microbe.
When iodide is the halide, iodination is detected [69
]. The fixed iodide can be localized in part in the phagosome by autoradiographic techniques [49
] and by the detection of radioiodide in the isolated phagosome [219
]. The bulk of the iodination appears to involve other neutrophil constituents [49
, 220
, 221
] and extracellular proteins [222
, 223
]; however, autoradiographic studies demonstrated the presence of silver grains lining the surface of the ingested organism [49
], indicating bacterial iodination as well. Chlorination and bromination also occur. Thus, free 3-chlorotyrosine and 3-bromotyrosine levels, used as markers of the reaction of MPO with H2O2 and chloride or bromide, rise in the peritoneal fluid of wild-type mice with experimentally induced sepsis but not (or to a considerably lesser degree) in septic mice deficient in MPO [207
]. The bromination observed in the absence of MPO may be a result of the presence of eosinophil peroxidase [224
]. 3-Chlorotyrosine has also been detected in tracheal aspirates from preterm infants, particularly those with respiratory distress [225
], in human atherosclerotic lesions [226
], in sputum specimens of patients with cystic fibrosis [227
], and in bronchoalveolar lavage fluid proteins of patients with acute respiratory distress syndrome, the latter in association with increased nitrotyrosine levels and MPO [228
]. Fluorescein-conjugated beads react with HOCl to form mono- and dichlorofluorescein [216
]. When human neutrophils were exposed to opsonized fluorescein-conjugated beads, 20 beads per cell became cell-associated, of which approximately two thirds were incorporated into sealed phagosomes. Near stoichiometric chlorination of the phagocytosed beads occurred [216
]. Of particular interest is the demonstration that bacteria sequestered in the phagosome are chlorinated by a MPO-dependent mechanism, as indicated by the presence of 3-chlorotyrosine and 3,5-dichlorotyrosine in bacterial proteins [229
, 230
]. In contrast, neutrophils failed to nitrate bacterial proteins in the phagosome under conditions in which chlorination was readily observed [230
]. Although it seems clear that HOCl is formed in adequate amounts to kill the ingested microorganisms, it would be expected to be scavenged to some degree if formed some distance from the microbe, as it travels through a fluid rich in scavengers, thus decreasing the amount of HOCl available for reaction with the ingested bacteria [229
]. However, chlorination of tyrosine residues of bacterial proteins does occur [229
, 230
], and this may be only the tip of the iceberg, as kinetically more favored (and likely more toxic) reactions of HOCl with, among others, sulfhydryl groups, iron-sulfur centers, and sulfur-ether groups would be expected to precede chlorination. Thus, although not all of the HOCl formed by leukocytes is used to attack the ingested organism, some of it is, which raises the question: how much is enough? The microbicidal power of HOCl is compatible with the need for only a portion of the HOCl formed.
H2O2 generation by neutrophils is required for optimum microbicidal activity
Enzymes that scavenge H2O2, such as catalase, protect certain organisms, e.g., coagulase-positive staphylococci, from the toxic effect of reagent H2O2 [231
, 232
] and neutrophils [233
] in vitro, and staphylococcal strains rich in catalase are more virulent in vivo [233
]. Furthermore, neutrophils from patients with CGD lack a respiratory burst, and the microbicidal defect in these cells can be reversed in part by the introduction of H2O2 into the cell [234
235
236
237
]. Glucose oxidase, which forms H2O2 without an apparent O intermediate, can be used for this purpose, indicating that H2O2 is effective even when the cells remain deficient in O. Finally, certain microorganisms, e.g., strains of streptococci, pneumococci, and lactobacilli, generate H2O2, and these organisms are killed well by CGD leukocytes [238
239
240
] and are rarely found in the lesions of infected patients. Presumably, they provide the H2O2 required for their own destruction by leukocytes that lack a cellular H2O2-generating system. This is supported by the finding that mutant strains of Streptococcus faecalis [241
] and Streptococcus pneumoniae [242
, 243
] with diminished H2O2 production are killed less well by CGD leukocytes than are the wild-type strains. These organisms also lack a heme catalase; however, the studies with mutant strains suggest that the level of H2O2 production may be more important than the catalase content in their susceptibility to killing by CGD leukocytes.
MPO is required for optimum microbicidal activity
Peroxidase inhibitors such as azide [244
, 245
], cyanide [244
, 245
], and sulfonamides [246
] decrease the microbicidal activity of normal neutrophils and have little or no effect on the microbicidal activity of MPO-deficient neutrophils, suggesting that they exert their effect on normal neutrophils largely by the inhibition of MPO. Neutrophil cytoplasts (neutroplasts) lack nuclei and are greatly depleted of cytoplasmic granules (and thus MPO) but have an intact respiratory burst [247
, 248
]. Neutroplasts phagocytose but do not kill Staphylococcus aureus unless the bacteria are coated with MPO [249
], suggesting that the respiratory burst is not sufficient for the killing of the organisms but that the additional presence of MPO is required. Similarly, stimulated neutroplasts do not lyse erythrocytes [250
] or inactivate 1-proteinase inhibitor [251
] unless MPO is added. Finally, human neutrophils, which lack MPO, have a microbicidal defect in vitro, although the defect is not as severe as in CGD. Thus, in 1969, Lehrer, Cline, and Hanifin [252
, 253
] described a diabetic patient with MPO deficiency and systemic candidiasis whose neutrophils had a prolonged candidacidal defect in vitro, whereas their staphylocidal activity was characterized by a lag period following which the organisms were killed. At this time, MPO deficiency was considered to be a rare event. However, the introduction of automated white blood cell counting techniques, which used the peroxidase stain, indicated that hereditary MPO deficiency was not uncommon in Europe and America (one in 2000–4000 [254
, 255
]), although it was less common in Japan (complete deficiency, one in 57,135 [256
]). Although some of these patients had clinical infections, most were well despite the demonstration of a neutrophil microbicidal defect in vitro [254
, 255
, 257
, 258
]. In one study comparing 100 patients with total or subtotal MPO deficiency to 118 with normal MPO levels, there was a statistically significant, higher incidence of severe infection and chronic inflammatory processes in the deficient patients [259
].
Does the microbicidal activity of human MPO-deficient leukocytes accurately reflect the contribution of MPO to the microbicidal activity of normal cells? Evidence has been provided suggesting that it may not [244
]. Figure 5
demonstrates the effect of the peroxidase inhibitor azide on the microbicidal activity of normal and MPO-deficient neutrophils on three organisms, Lactobacillus acidophilus, coagulase-negative staphylococci, and Candida tropicalis. As reported earlier [252
, 253
], the organisms were killed less well by MPO-deficient than by normal neutrophils. Azide markedly decreased the microbicidal activity of normal neutrophils and had no effect on the microbicidal activity of MPO-deficient neutrophils, suggesting that it exerts its effect on normal cells by the inhibition of MPO. Of particular interest is the observation that the microbicidal activity of MPO-deficient leukocytes is greater than that of azide-treated, normal cells [244
]. This suggests that the contribution of MPO to the microbicidal activity of normal neutrophils may be greater than that suggested by studies with MPO-deficient neutrophils, as the latter cells appear to have adapted to the long-term absence of MPO with an increase in the activity of the MPO-independent (azide-insensitive) antimicrobial systems. Thus, the microbicidal activity of MPO-deficient cells appears to underestimate the contribution of MPO to the killing by normal cells.
Mice that lack MPO have an increased susceptibility to infection
under some experimental conditions but not others. Thus, MPO-knockout
mice have an increased susceptibility to
Candida albicans infection,
whereas the clearance of
S. aureas is normal [
260
]. MPO-deficient
mice are also considerably more susceptible to the development
of pulmonary infection following the intranasal instillation
of
C. albicans,
C. tropicalis,
Trichosporon asahii, and
Pseudomonas aeruginosa, whereas susceptibility to infections with
Aspergillus fumigatus and
Klebsiella pneumoniae is increased to a lesser
degree, and susceptibility to
Candida glabrata, Cryptococcus neoformans,
S. aureus, and
S. pneumoniae is comparable to that
of the wild-type strain [
261
]. Further, mice lacking MPO are
more susceptible to intra-abdominal infection and sepsis following
cecal ligation and puncture than are wild-type mice [
207
].
In a study comparing the susceptibility to intraperitoneal
C. albicans infection of wild-type, MPO-deficient, and CGD mice,
it was concluded that when the fungal load is low, ROS formed
by the NADPH oxidase of neutrophils are adequate to control
infection in the absence of MPO, but that at high fungal load,
respiratory burst products and MPO are needed [
262
]. Similarly,
CGD and MPO-deficient mice are more susceptible to pulmonary
infection with
C. albicans or
A. fumigatus than are normal mice,
and the infection of CGD mice is more severe than that of MPO-deficient
mice [
263
]. It should be emphasized, however, that mice are
not humans and that the findings with the mouse model do not
necessarily translate to humans. For example, the MPO level
of mouse neutrophils is approximately 10% of that of human cells.
Further, the inducible NO· synthase system with its associated
microbicidal activity appears to be much more highly developed
in rodent than in human phagocytes (see below, Reactive nitrogen
intermediates) and is thus more likely to substitute for the
MPO system in mice when MPO is absent. A comparison of the microbicidal
activity of normal and MPO knockout mice when NO· synthase
is also absent would be of interest in this regard.
It can be concluded from these studies that MPO is involved in the microbicidal activity of normal neutrophils, particularly in the early post-phagocytic period or when the microbial challenge is high, but that MPO-independent antimicrobial systems develop more slowly but are ultimately effective in MPO-deficient leukocytes, particularly when the microbial challenge is low. It should be emphasized that organisms differ in their susceptibility to oxygen-dependent antimicrobial systems. Thus E. coli are killed well by CGD and MPO-deficient leukocytes [264
], fungi are particularly dependent on MPO for killing [252
], and staphylococci are intermediate [253
]. However, even if the MPO system is not required for the killing of a particular organism, it may normally do so in the early post-phagocytic period as a result of its rapid mobilization and power.
MPO-INDEPENDENT ANTIMICOBIAL SYSTEMS
What is the nature of the azide-insensitive (i.e., MPO-independent)
antimicrobial systems of phagocytes? These may include ROS operating
in the absence of MPO, reactive nitrogen intermediates, intravacuolar
acidity, cationic peptides and proteins, and proteases. These
systems may contribute to the microbicidal activity of phagocytes
in the presence as well as in the absence of MPO.
ROS operating in the absence of MPO
The staphylocidal activity of MPO-deficient neutrophils is inhibited by anaerobiosis, indicating that the microbicidal activity is at least in part dependent on oxygen ([222
]; see p. 437 in ref. [265
]). The respiratory burst of murine [260
] and human [222
, 266
267
268
269
270
271
272
273
274
] MPO-deficient leukocytes has been shown in a number of studies to be greater than normal, which may be a result of at least two mechanisms. First, MPO may be required for the termination of the respiratory burst [275
], and thus, its absence would lead to increased production of toxic oxygen metabolites. Second, as H2O2 is degraded in part by the MPO system in neutrophils, the absence of MPO would be expected to lead to a build-up of H2O2 as well as that of other oxidants dependent on H2O2 for their formation. These oxidants may eventually kill or at least contribute to the killing of the ingested organisms in the absence of MPO.
O and H2O2 are recognized products of the respiratory burst of phagocytes, which do not require MPO for their formation. O could theoretically be directly toxic to ingested organisms. However, many biologically important compounds react rather sluggishly with O, leading to the suggestion that O does not have the necessary reactivity to be directly toxic to ingested organisms. However, following are a few words of caution. The chemical reactivity of O is increased considerably in a nonpolar environment, as exists in the hydrophobic region of a membrane, where the reactions of O are not in competition with the proton-requiring dismutation reaction. Under these conditions, O is a powerful base with considerable nucleophilicity and reducing activity. Further, the protonated form HO2· is a considerably stronger oxidant than is O, raising the possibility that a local fall in pH, as might occur at a membrane surface or within a phagosome, may cause a shift in the HO2· 
O equilibrium toward the more potent, protonated form, with localized damage to a membrane or ingested organism. Further, the low, steady-state concentration of O would limit its dissipation by spontaneous dismutation, and this together with its relatively low reactivity allow it to diffuse over significant distances as through the ion channels of some cell membranes [276
], where it may be toxic at a distance through the formation of more reactive oxidants. H2O2 alone has antimicrobial properties at concentrations higher than those needed to generate toxic amounts of HOCl by the MPO system and thus, may contribute to the microbicidal activity of MPO-deficient phagocytes.
Reactive nitrogen intermediates (RNI)
Nitric oxide (NO·) is a recognized product of a cytokine-inducible NO· synthase in murine phagocytes where it contributes to microbicidal activity [277
]. It acts synergistically with ROS under some conditions [278
]. The production of NO· by human phagocytes, however, has been more difficult to demonstrate. Thus, in early studies, NO· formation by human phagocytes could not be detected under conditions in which NO· formation by murine phagocytes was readily apparent [279
280
281
]. However, human neutrophils appropriately stimulated have been shown to contain an inducible NO· synthase (iNOS) [282
283
284
], as do tissue macrophages from infected humans [285
286
287
288
]. It has been concluded that although human mononuclear phagocytes can produce iNOS when appropriately stimulated, NO· production by these cells is very low as compared with mouse phagocytes [289
, 290
].
NO· reacts with O to form peroxynitrite (ONO2–) [291
292
293
] (Fig. 6
), which can oxidize nonprotein and protein sulfdryl groups [294
]. ONO2–, at acid pH, is protonated to form peroxynitrous acid (ONO2H), which decomposes to form a strong oxidant with the properties of ·OH [295
, 296
]. ONO2–/ONO2H has bactericidal properties [297
298
299
] and thus may contribute to the MPO-independent antimicrobial activity of phagocytes. However, the contribution of ONO2–/ONO2H would be expected to be greater in rodent than in human phagocytes. Carbon dioxide (CO2) reacts with ONO2– to form the ·ONO2CO2– adduct with a corresponding loss of bactericidal activity [299
, 300
].
Nitration of tyrosine and tyrosine residues of proteins has
been used as a marker for the production of RNI. Initially,
the mechanism proposed for the induction of nitration by phagocytes
was the reaction of NO· with O
to form ONO
2–/ONO
2H,
which was the nitrating species. Recently, doubt has been cast
on the essential role of peroxynitrite in nitration by phagocytes
[
301
] and evidence presented supporting a role for peroxidase
in the nitration process [
203
,
302
,
303
] (for commentary,
see ref. [
304
]). Nitrite is converted to a nitrating species,
and tyrosine is oxidized to the tyrosyl radical by MPO and H
2O
2 [
305
306
307
]. Further, phagocytes activated in medium containing
nitrite can generate nitrating species through a MPO-dependent
mechanism [
306
,
308
], and murine macrophages activated by
immunological stimuli can generate the nitrite required for
catalysis of the nitration reaction by peroxidase and H
2O
2 [
302
].
Nitration of free or protein-associated tyrosine has been detected
in areas of inflammation [
309
]. However, the absence of nitration
in the phagosome, even at nitrite concentrations up to 0.1 M
[
310
], would suggest that the oxidation of nitrite is not a
major source of oxidants in the phagosome, although the oxidation
of nitrite in the extracellular fluid by MPO and H
2O
2 released
from phagocytes may occur in vivo [
311
]. The formation of nitrating
and chlorinating species, possibly nitryl chloride (Cl–NO
2)
or chlorine nitrite (Cl–ONO), by reaction of nitrite with
HOCl with their involvement in tissue injury, has been proposed
[
312
]. Paradoxically, the toxicity of the MPO-H
2O
2-chloride
system or its product HOCl is inhibited by nitrite [
202
,
313
314
315
316
]
as a result of an interaction between nitrite and HOCl, which
results in the stoichiometric removal of both [
202
]. Further,
nitrite or a product of its oxidation can bind to the heme prosthetic
group of MPO and thus modulate its activity [
202
,
307
,
317
318
319
].
Whether nitrite influences the MPO-mediated antimicrobial system
in the phagosome positively or negatively remains to be established.
Intraphagosomal acidity
Studies of intraphagosomal pH have yielded conflicting results. In early studies, a fall in intraphagosomal pH was observed (for review, see pp. 447 and 448 in ref. [265
]), although the extent of the fall varied. Thus, Metchnikoff [320
] first reported that "the staining of the ingested elements indicates a feebly acid reaction inside the phagocytes." Further, he stated that "while the phagocyte is still living the acid juice which fills the vacuoles or permeates the ingested organisms does not mix with the protoplasm which is always alkaline." Subsequently, Rous [321
, 322
] reported that the "intragranular" pH of peritoneal exudate cells in mice or rats was 3.0 or below, Sprick [323
] found the intraphagosomal pH surrounding mycobacteria ingested by mouse or guinea pig intraperitoneal cells to be 4.7–5.5, Pavlov and Solov’ev [324
] found the pH surrounding bacteria ingested by mouse peritoneal cells to be 4.7–5.2, and Jensen and Bainton [325
] reported that the intraphagosomal pH in rat peritoneal polymorphonuclear leukocytes (PMNs) fell to 6.5 in 3 min and to 4.0 in 7–15 min following the ingestion of yeast particles. In these studies, microorganisms coated with indicator dyes were used in vivo. Mandell [326
], using human PMNs ingesting indicator dye-stained candida in vitro, found a fall in intraphagosomal pH to 6.0–6.5. Kakinuma [327
], using the 5,5-dimethyl-2,4-oxazolidinedione method for determining intracellular pH, estimated the intraphagosomal pH of guinea pig PMNs to be 5.5–6.0. These findings led to the suggestion that intraphagosomal acidity may limit the growth of certain ingested microorganisms.
More recent studies, however, have suggested an initial rise in pH followed by a fall. Thus, Segal et al. [328
] reported an initial rise in intraphagosomal pH to 7.75 within the first 2 min of phagocytosis by human neutrophils, followed by a slower fall in pH to 6.0–6.5 in 2 h. Similarly, Geisow et al. [329
] described an initial rise in intraphagosomal pH in mouse peritoneal macrophages to 7.75 in 1.5–2 min, followed by a fall to levels below pH 6 at 7 min. Cech and Lehrer [330
], using human neutrophils, reported an initial increase in pH to 7.8 in 5 min followed by a fall in pH to 6.35 in 30 min and 5.68 in 60 min. Also, Jiang et al. [216
] reported a slight rise in pH to 7.5–7.7 over the first 15 min following phagocytosis by human neutrophils, followed by a slow decline to about pH 7.0 in 60 min. These findings would suggest that a fall in pH is unlikely to contribute to antimicrobial activity during the immediate post-phagocytic period but may do so later. It should be emphasized, however, that the intraphagosomal chlorination of the probes used to measure pH may alter their spectral properties, thus making their use for the measurement of pH equivocal [331
]. Under conditions in which alteration in the properties of the fluorescent pH probe by chlorination was minimized by the inhibition of MPO, initial alkalinization of the phagosome was not detected, and the pH remained near neutral for at least 20 min [332
]. When the NADPH oxidase was inhibited by diphenylene iodinium, a rapid acidification of the phagosome occurred, and the pH reached 5.1 in 2–8 min [332
]. It is of interest in this regard that in CGD leukocytes (in which the respiratory burst and thus the MPO system are not operative), there is not an initial alkalinization but rather an immediate and rapid fall in pH to 6.7 in 2 min, with the final intraphagosomal pH being 5.5 [328
]. Thus, measurements of intraphagosomal pH varied strikingly under different experimental conditions and may, to some degree, be artifactual due to the altered properties of chlorinated probes.
The gp9l phox membrane component of the NADPH oxidase of neutrophils has been reported to act as an H+ channel, conducting protons across the membrane into the extracellular fluid and/or phagosome [333
, 334
]. However, other studies have suggested that the H+ channel is separate from the NADPH oxidase [335
336
337
]. Extracellular proton release, which is associated with the respiratory burst of normal neutrophils, was not seen when CGD neutrophils were used [338
], despite the rapid and immediate fall in intraphagosomal pH [328
].
Cationic peptides and proteins
A variety of cationic peptides and proteins present in leukocyte granules has been implicated in the microbicidal activity of phagocytes. These include defensins, seprocidins, bactericidal/permeability-increasing protein, lysozyme, cathelicidins, phospholipase A2, and lactoferrin [339
340
341
342
]. Figure 7
compares the staphylocidal activity of a human neutrophil granule cationic protein preparation provided by Olsson and Venge [343
] to that of the MPO system (see p. 459 in ref. [265
]). The cationic proteins at a concentration of 50 µg/ml had a small but significant staphylocidal effect after 2 h of incubation, whereas the MPO system, with MPO at 2 µg/ml, was strongly bactericidal at the earliest time period used (7.5 min). These findings do not necessarily reflect the relative roles of these systems under other experimental conditions, with other peptide or protein preparations, against other microorganisms or in the intact cell where oxygen may be limiting and the cationic protein concentration high. However, it does emphasize the greater microbicidal potential of the MPO system against some organisms.
Proteases
In a recent study [
344
], mice deficient in neutrophil granule
elastase were shown to have an increased susceptibility to
S. aureus but not to
C. albicans infection, and mice deficient
in cathepsin G had an increased susceptibility to
C. albicans but not to
S. aureus infection in vivo (for comments, see refs.
[
345
346
347
]). Neutrophils from these animals had a corresponding
killing defect in vitro. Mice deficient in neutrophil elastase
and/or cathepsin G also had increased susceptibility to
A. fumigatus infection [
348
]. Other studies suggested that mice deficient
in neutrophil elastase were more susceptible to infection with
K. pneumoniae and
E. coli infection but not to infection with
S. aureus [
349
,
350
]. Further, cathepsin G-deficient mice
have been reported to kill
S. aureus, K. pneumoniae, and
E. coli normally [
351
]. Thus, the susceptibility of microorganisms
to proteases appears to vary under different experimental conditions.
Neutrophil elastase has been reported to exert its toxic effect
on
E. coli by the degradation of the organism’s outer
membrane protein A (OmpA) [
352
], and neutrophil elastase, cathepsin
G, and proteinase 3 can cleave the flagellin of Gram-negative
organisms and thus influence the inflammatory response [
353
].
It has been proposed that the influx of O into the phagosome and its dismutation there consume protons leading to a small rise in intraphagosomal pH, which would facilitate antimicrobial activity of granule proteins with alkaline pH optima [328
]. Further, an influx of high concentrations of K+ through a Ca2+-activated K+ channel occurs in an attempt to maintain charge neutrality [344
, 354
] (for discussion of the role of K+, see refs. [355
, 356
]). The resultant alkalinity and hypertonicity may result in the release of cationic proteins and neutral proteases with antimicrobial activity from intraphagosomal complexes with proteoglycans. It is of interest in this regard that microbial killing and digestion were abolished when the K+ channel was blocked, despite normal NADPH oxidase activity, phagocytosis, and iodination [354
]. It has been recently proposed that ion movement and ROS contribute to microbial killing by phagocytes, with the ion movement being most significant at low O production [357
].
POTENTIAL TARGETS OF THE MPO SYSTEM
The MPO-H
2O
2-halide system, like the household bleach Clorox,
is broadly toxic in vitro. It is toxic to a variety of microorganisms
(bacteria, fungi, viruses, protozoa, amoebae, helminths), bacterial
toxins, intact mammalian cells (tumor cells, granulocytes, lymphocytes,
erythrocytes, spermatozoa), and low molecular weight mediators
(chemotactic factors,
1-proteinase inhibitor, leukotrienes).
The MPO system, although generally inhibitory in its actions,
also can be stimulatory at low levels, as for example, in the
stimulation of platelet and mast cell secretion and the activation
of certain proteases (e.g., collagenase, gelatinase; for review,
see refs. [
12
,
358
]). Other proteases, e.g., matrix metalloproteinase-7
[
359
], are inhibited by the MPO system. HIV-1 is given here
as an example of a potential target of the MPO system and the
approach used to detect an effect of the MPO system on survival.
In this instance, ROS, formed by phagocytes, may have opposing
effects, i.e., a viricidal effect as a result of the MPO system
and the stimulation of viral replication as a result of activation
of the HIV-1 long-terminal repeat (LTR) by H
2O
2.
HIV-1: viricidal effect
The MPO-H2O2-halide system is strongly toxic to HIV-1, as measured by the inability of the virus to replicate in the lymphocyte cell line CEM [134
]. The MPO could be replaced by eosinophil peroxidase (EPO) [360
], and the H2O2 could be replaced by a H2O2-generating enzyme system, such as amine oxidase [361
]. Chloride, bromide, iodide, and thiocyanate ions could meet the halide requirement of the MPO system [134
], and bromide, iodide, and thiocyanate could be used by the EPO system [360
]. H2O2-generating lactobacilli are viricidal alone at high concentration to HIV-1, in part as a result of the formation of H2O2, and when the lactobacilli are decreased to a level where they are no longer viricidal alone, the further addition of MPO and a halide restores viricidal activity [134
]. Peroxidase [132
] and H2O2-generating lactobacilli [130
] are present in the vaginal fluid of most women, raising the possibility that they may influence the heterosexual transmission of HIV-1 through their toxic effect on the virus. Neutrophils [362
] and monocytes [363
], when appropriately stimulated, were also toxic to HIV-1, an effect that was inhibited by catalase, implicating H2O2, and by the peroxidase inhibitor azide, implicating MPO. Activity was also lost when chloride was replaced by sulfate in the medium. Stimulated cells from CGD patients were not viricidal unless H2O2 was added, and the viricidal activity of the H2O2-supplemented cells was inhibited by azide implicating endogenous MPO. Further, stimulated neutrophils or monocytes from patients with hereditary MPO deficiency were not viricidal unless MPO was added, and the viricidal effect of the MPO-supplemented cells was inhibited by catalase, implicating endogenously formed H2O2. When monocytes are allowed to differentiate in culture to macrophages, MPO is lost, and the respiratory burst and thus, H2O2 formation is greatly decreased. The viricidal effect on HIV-1 of 3- to 9-day monocyte-derived macrophages was lost unless MPO was added, whereas when 12-day monocyte-derived macrophages were used, MPO did not restore activity unless the cells were pretreated with interferon-
, which increases the respiratory burst of macrophages [364
]. Stimulated human eosinophils also are viricidal to HIV-1 through the action of a peroxidase (EPO)-H2O2 system [360
].
HIV-1: activation of the LTR
H2O2 can activate the HIV-l LTR and increase HIV-1 production by latently infected cell lines [365
366
367
], at least in part by activation of the nuclear transcription factor NF-
B [366
]. H2O2-induced activation of the HIV-1 LTR and stimulation of virus production are greatly enhanced by vanadate, presumably as a result of the reaction of H2O2 with vanadate to form peroxides of vanadate, which have potent biological properties [367
]. Activation of the HIV-1 LTR and viral replication by H2O2 are also strongly stimulated by polar, aprotic solvents such as dimethylsulfoxide, dimethylacetamide, and dimethylformamide [368
]. H2O2-generating lactobacilli can activate the HIV-l LTR in Jurkat T lymphocytes, an effect that is enhanced by vanadate and inhibited by catalase, implicating H2O2 [369
]. Thus, H2O2 generated by vaginal lactobacilli may influence viral replication in two opposing ways, by its viricidal effect, particularly when supplemented with peroxidase and a halide, and by the stimulation of viral replication by activation of the LTR.
Human neutrophils stimulated by phorbal myristate acetate (PMA) strongly activated the HIV-1 LTR in Jurkat T lymphocytes [370
]. Activation was inhibited by catalase, was potentiated by vanadate, and was not observed when normal neutrophils were replaced by neutrophils that lack a respiratory burst, i.e., from patients with CGD, implicating H2O2. In contrast to its inhibitory effect on the viricidal effect of stimulated neutrophils [362
], azide increased LTR activation by PMA- and opsonized zymosan-stimulated neutrophils, presumably by inhibiting the degradation of H2O2 [370
]. Thus, products of the respiratory burst of neutrophils can have a dual effect on HIV-1, a viricidal effect through the release of components of the MPO-H2O2-halide system and a viral-promoting effect through activation of the LTR.
OTHER BENEFICIAL FUNCTIONS OF MPO
The studies described above strongly suggest that the primary
physiologic function of MPO is to kill microorganisms in neutrophils
and monocytes, and to do this, it forms highly reactive halide
(particularly chloride)-derived oxidants in the confines of
the phagosome. Does MPO have other "normal" functions beneficial
to the host? Agner [
371
,
372
] proposed that MPO played a protective
role in infectious diseases by the detoxification of microbial
toxins such as diphtheria or tetanus toxin. The MPO system also
can induce platelet [
373
,
374
] and mast cell secretion [
375
376
377
]
and can activate certain proteases in vitro [
12
]. Lanza et
al. [
378
379
380
381
] have reported a high incidence of malignancy
in patients with complete MPO deficiency and have raised the
possibility that MPO-dependent tumoricidal activity may be required
to prevent the progression of some tumors. Kutter et al. [
259
],
however, could not detect an increase in malignancies in their
group of MPO-deficient patients. Persons who inherit two copies
of an allele with a single-base substitution in the promoter
region of the MPO gene (which markedly reduces expression of
this gene) have been reported to have a decreased risk of lung
cancer [
382
]. To my knowledge, a change in susceptibility to
tumors has not been detected in MPO-deficient mice.
My initial goal was to find a biologic role for peroxidases in the mode of action of the thyroid hormones and estrogens. Although thyroxine can substitute for the halide in the MPO-H2O2-halide antimicrobial system [69
], throxine is deiodinated under these conditions [204
, 205
], raising the possibility that the released iodide may be the required microbicidal component. The thyroid hormones have, however, been reported to stimulate the generation of chlorinating oxidants by the MPO-H2O2-chloride system [383
, 384
]. Impaired thyroid hormone or estrogen response has not been noted in patients with MPO deficiency, suggesting that the phenolic hormones do not require MPO for their action. Thyroxine is synthesized first by the iodination of tyrosine residues in thyroglobulin and then by the coupling of two diiodotyrosine residues to form thyroxine. The iodination and coupling reactions are catalyzed by a thyroid peroxidase. MPO is also capable of this synthesis [385
, 386
]; however, there is no evidence that it does so in vivo. On the contrary, stimulated phagocytes can inactivate thyroxine through a MPO-dependent deiodination reaction [204
, 205
]. The MPO system also inactivates estrogens [387
], and the estrogens are covalently bound to cellular constituents when incubated with phagocytes during phagocytosis [388
]. These findings raise the possibility that inactivation of thyroxine and estrogens by the MPO system may occur at sites of inflammation. In summary, a physiologic role for MPO, distinct from its contribution to the phagocyte antimicrobial armamentarium, remains to be established.
TISSUE INJURY
MPO can be released to the outside of the cell, as can H
2O
2,
raising the potential for damage to an extracellular target.
There are two types of extracellular targets: those to which
the PMN is adherent and those to which it is not. When the PMN
is adherent to a target too large to be ingested, as for example,
to a multicellular organism or a cell membrane coated with antibody
and/or complement, the PMN flattens on the surface of the target
and is stimulated with the release of MPO into a walled-off
pocket of space between the cell and the target to which it
is adherent. H
2O
2 formed by the stimulated PMN is released into
the pocket, and toxicity is induced in a manner similar to that
occurring in an intracellular phagosome containing an ingested
microorganism.
Toxicity to a target to which the PMN is not adherent can occur when MPO is released into the extracellular fluid by leakage during phagocytosis, by cell lysis, or when the PMN is exposed to a variety of soluble stimuli. A major deterrent to the production of toxicity at a distance by ROS produced by phagocytes is the presence of scavengers in the intervening fluid. Thus, proteins such as serum albumin, as well as a number of low molecular weight-reducing agents, react rapidly with the highly reactive products of the MPO system and prevent them from reaching a sensitive target of biological importance. We are thus protected from indiscriminant damage by phagocyte-produced oxidants. By definition, the more reactive the product of the MPO system, the more likely it will be scavenged. Under conditions in which HOCl or chlorine is readily scavenged, less-reactive PMN products, such as certain chloramines or H2O2, may penetrate the extracellular fluid to be toxic at a distance. MPO and EPO are strongly basic proteins and thus bind avidly to negatively charged surfaces such as cell membranes. H2O2, reaching that site from a distance, can react with the peroxidase located there to induce damage. MPO, when bound to albumin, may be transported across the endothelium by reaction with albumin-binding proteins located in caveolae [389
].
Can the MPO system damage normal tissue and thus contribute to disease? There is considerable evidence to suggest that it has this potential [12
, 258
].
Carcinogenesis
A number of studies have implicated MPO in the development of malignancies. A polymorphic site is located 463 bp upstream of the MPO gene (–463 G/A) in the Alu hormone-responsive element of the promoter region. The G allele acts as a strong SP1 transcription factor-binding site, which reacts with SP1 to increase MPO expression [390
]. This allele is enhanced in patients with acute myeloid leukemia in association with high levels of MPO mRNA and expression [391
]. The G-to-A nucleotide base shift, which is associated with decreased SP1 binding and thus lower MPO gene expression, has been associated with an overall decreased risk for lung cancer by some investigators [382
, 392
393
394
395
396
397
398
399
400
401
] (for commentary, see ref. [402
]) but not by others [403
404
405
], and with a decreased risk of larynx cancer [392
], bladder cancer [406
], and hepatoblastoma [407
]. Although G/A polymorphism alters transcription rates, there are few studies indicating corresponding changes in MPO protein or enzyme activity. The MPO system, in cell-free form or in intact, stimulated neutrophils, can catalyze the conversion of certain procarcinogens to their carcinogenic form [408
409
410
411
] and in this way, may contribute to the development of malignancies. Further, the formation of 5-chlorouracil and 5-bromouracil by the MPO (or EPO) system and their incorporation into nuclear DNA can be mutagenic [412
, 413
]. The MPO –463 AA/AG genotypes are associated with reduced benzo[a]pyrene diol epoxy DNA adduct formation in skin of tar-treated patients and thus decreased carcinogenesis [414
].
Renal injury
MPO has been implicated in the pathogenesis of renal disease (for review, see ref. [415
]). There is considerable evidence that neutrophils mediate glomerular injury in certain experimental models of nephritis [416
]. This is best documented in antiglomerular basement membrane nephritis in which antibody to glomerular basement membrane forms an antigen-antibody complex on the basement membrane, which activates complement to form chemotactic factors, which attract neutrophils to the region. Glomerular injury is evidenced by proteinuria, and the involvement of neutrophils in the damage is suggested by the prevention of injury by depletion of neutrophils with antineutrophil serum or cytotoxic agents and the reinstitution of injury by the intravenous (i.v.) infusion of neutrophils to a leukocyte-depleted animal. The mechanism by which neutrophils induce glomerular injury may include the release of lysosomal hydrolases, cationic peptides, and ROS, particularly H2O2, operating in the absence or presence of MPO. What is the evidence for the involvement of the MPO system?
MPO, when infused into the renal artery of the rat, binds to the glomerular basement membrane, as indicated by light and electron microscopic examination of sections stained for peroxidase by the diaminobenzidine method [417
]. MPO was detected 1 min following perfusion throughout the basement membrane, with concentration in the subepithelial space along the base of the epithelial cell-foot processes. MPO is a highly cationic protein and may bind to the glomerular basement membrane through ionic bonds with negatively charged groups on sialoglycoproteins and heparin sulfate proteoglycans. When the infusion of MPO into the renal artery is followed by an infusion of H2O2, renal damage was indicated by an increased 24-h urinary protein excretion, which was not observed following the infusion of MPO or H2O2 alone. Morphologically, light microscopy at 4 h revealed a reduction in nuclear staining of resident glomerular cells, cell swelling, and a wrinking of the glomerular basement membrane [417
, 418
]. At 24 h, these changes were more prominent with the occlusion of many capillary loops with a weakly eosinophilic granular material. Electron microscopy at 4 h indicated the presence of endothelial cell swelling with occasional denudation. Platelets were frequently present in the capillary lumen, whereas infiltrating leukocytes were not common. Focal epithelial cell foot process effacement was present, but no discontinuities in the glomerular basement membrane were evident.
These studies suggest that MPO bound to the glomerular basement membrane can react with the infused H2O2 in a chloride-containing medium to induce glomerular injury. This injury was associated with in vivo iodination of glomeruli when radioiodide was added to the last perfusate, and electron microscopic autoradiography revealed the presence of silver grains along the glomerular basement membrane [417
]. These findings indicate that MPO can react with H2O2 to oxidize iodide to a form that binds in covalent linkage to adjacent glomerular basement membrane components.
In the studies described above, glomerular injury was induced by infusion of MPO and H2O2 into the renal artery of normal rats. Does this system contribute to renal damage in a neutrophil-dependent model of glomerulonephritis? The model used involved the infusion of concanavalin A (Con A) into the renal artery, which bound to the glomerular basement membrane, serving as a planted antigen [419
]. When this infusion was followed by an infusion of rabbit anticon A antibody, an antigen-antibody complex formed on the basement membrane, which attracted neutrophils to the region. Proteinuria occurred, which was not seen when the anticon A was replaced by normal rabbit immunoglobulin G (IgG) and was significantly reduced but not abolished when the animals were neutrophil-depleted with antineutrophil antibody. Iodination of the glomeruli was evident when radioiodide was administered i.v. after the Con A-anticon A infusion and was not seen in control rats given Con A and normal rabbit IgG or when the rats were neutrophil-depleted with antineutrophil antibody. These findings are compatible with a contribution by the MPO-H2O2-halide system to the renal damage in experimental neutrophil-dependent glomerulonephritis.
A role for MPO in the glomerular injury observed in rapidly progressive glomerulonephritis in humans was suggested by the presence of MPO in the glomeruli of most patients with this condition in association with an increase in the titer of MPO-specific, antineutrophil cytoplasmic antibody (MPO-ANCA) [420
]. Further evidence of the involvement of MPO-ANCA in a mouse model of vasculitis and glomerulonephritis using MPO knockout mice immunized with mouse MPO has been presented [421
] (for commentary, see ref. [422
]). The activation of tumor necrosis factor -primed neutrophils by MPO-ANCA has an absolute requirement for cellular MPO [423
]. The GG genotype of the –463 G/A MPO promoter polymorphism was found to be associated with an increased risk of MPO-ANCA-associated vasculitis in females but not males, and the A allele was associated with an increased incidence of relapses and an earlier age of diagnosis [424
]. The G-to-A conversion at position –463 is also associated with a lower prevalence of cardiovascular complications in end-stage renal disease [425
]. An interaction between MPO-ANCA and glomerulus-associated MPO may produce changes similar to those observed in the Con A-anticon A model described above. Similarly, recent studies have proposed a role for MPO and MPO-ANCA in the injury observed in a mouse model of coronary artery vasculitis [426
, 427
]. MPO and HOCl-modified proteins have been demonstrated in diseased human renal tissue, often in association [428
], and 3- chlorotyrosine, a specific marker of the MPO-H2O2-halide system, was detected in the plasma proteins of chronic hemodialysis patients [429
].
Lung injury
MPO has been implicated in the induction of lung injury. In vivo studies, in which the intratracheal infusion of glucose oxidase (as a source of H2O2) and peroxidase (LPO, MPO) into rats produced severe acute lung injury, which progressed to interstitial fibrosis under conditions in which infusion of glucose oxidase or peroxidase alone produced little damage [430
]. The alveolar epithelial lining fluid of most patients with idiopathic pulmonary fibrosis contains increased levels of MPO and inflammatory cells, which spontaneously released increased amounts of H2O2. This is compatible with the MPO system playing a role in the epithelial cell injury found in this disorder in humans [431
]. Further, protein carbonyl [432
] and 3-chlorotyrosine [225
] levels, which are markers of protein damage by the MPO system, were elevated in tracheal asperates of premature infants. 3-Chlorotyrosine levels were high in infants with low birth rates or who developed chronic lung disease and correlated strongly with MPO levels [225
].
Atherosclerosis
Of particular recent interest is the proposed involvement of MPO in the development of atherosclerosis [433
434
435
436
437
438
439
400
401
442
]. MPO binds to low-density lipoproteins (LDL) [443
], and under appropriate conditions, the LDL modified by MPO-catalyzed reactions is taken up by macrophages in increased amounts, converting them into the lipid-laden foam cells characteristic of the early atherosclerotic lesion [164
, 444
, 445
]. The oxidation of chloride [226
, 446
447
448
], bromide [449
], thiocyanate [450
], nitrite [451
, 452
], or tyrosine [179
, 453
] by MPO and H2O2 can form intermediates capable of the oxidative modification of LDL (or high-density lipoproteins [454
, 455
]), with the chloride-dependent formation of HOCl being likely the most important. The active tyrosine-derived oxidant can be the tyrosyl radical [179
, 456
, 457
] or the product of tyrosine oxidative deamination, p-hydroxyphenylacetaldehyde [453
, 458
]. The detection of MPO [459
460
461
] and specific markers of MPO-catalyzed halogenation [226
, 460
, 462
463
464
465
466
] in human atherosclerotic lesions, often colocalized [460
], is compatible with the involvement of MPO in the development of atherosclerosis in vivo. Nitration of LDL [467
] in human atherosclerotic lesions [467
, 468
] also occurs, and although nitration reactions can be catalyzed by MPO in the presence of nitrite [469
], other mechanisms for the generation of nitrating species exist. Serum/plasma protein-associated nitrotyrosine [470
] and plasma LDL 3-chlorotyrosine [455
] levels are elevated in patients with coronary artery disease, raising the possibility that these changes may serve as a marker of this condition. Nitrotyrosine elevation was modulated by statin therapy [470
]. Chlorination of LDL or its associated protein, apolipoprotein A-1 (APOA-1), impairs the removal of cholesterol from cultured cells by adenosine 5'-triphosphate-binding cassette transporter A1(ABCA-1)-dependent cholesterol transport [455
], suggesting a mechanism for the promotion of atherogenesis by MPO-catalyzed reactions.
It should be emphasized that the presence of MPO in or adjacent to pathologic lesions does not necessarily implicate it in the pathologic process. The detection of chemical markers of MPO-catalyzed reactions in the lesion suggests that at some point, the MPO was active. But did that activity contribute to the disease? Is there more definitive evidence for MPO involvement in atherosclerosis in vivo? Recent evidence using gp9lphox and MPO knockout mice has suggested that MPO-dependent reactions are not required for the initiation of atherosclerosis in mice. Gp91phox is the component of the NADPH oxidase of phagocytes most commonly defective in CGD, and mice deficient in this protein have phagocytes that lack a respiratory burst and thus, H2O2 production. These animals develop atherosclerosis normally on a high-fat diet. APO-E-deficient mice develop atherosclerosis on a normal diet. Atherosclerotic plaque development was similar in APO-E-deficient mice to that seen in CGD mice crossed with APO-E-deficient mice [471
]. These studies do not support the involvement of the products of the respiratory burst of phagocytes in the development of atherosclerosis in mice. Other sources of H2O2 for use by MPO, e.g., vascular NAD(P)H oxidase, may be available. Neutrophils from MPO-knockout mice, when stimulated by PMA, can oxidize LDL, although they are not as effective as neutrophils from wild-type mice in this regard [472
]. This suggests that MPO is not essential for the oxidation of LDL by neutrophils in this species. The oxidation by cells from wild-type and MPO-deficient mice was completely inhibited by SOD, suggesting that it is a result of O rather than H2O2 generation by phagocytes. Brennan et al. [473
] (see ref. [474
] for commentary) used a model of atherosclerosis in which mice deficient in the LDL receptor were lethally irradiated, their bone marrow repopulated with wild-type or MPO-deficient cells, and the development of atherosclerosis on feeding the animals a high-fat, high-cholesterol diet monitored. No decrease in atherosclerosis was detected in the MPO-deficient mice; indeed the lesions were 50% larger than in the control animals. Further, in contrast to human atherosclerotic lesions, MPO and the marker of MPO reactivity, 3-chlorotyrosine, were not detected in greater amounts in the lesions of wild-type as compared with MPO-deficient mice.
These studies with MPO-deficient mice indicate that MPO is not required for the development of lesions in an experimental mouse model of atherosclerosis. However, this does not exclude the possibility of MPO involvement in human atherogenesis. Neutrophil MPO levels were significantly higher in patients with coronary heart disease than in normal controls [475
]. Variations in the MPO content of peripheral blood monocytes in coronary heart disease were not determined in this study. Further, increased plasma [476
] or serum [477
] MPO levels in patients with coronary artery disease may serve to identify patients with an increased risk for further cardiovascular events (see ref. [478
] for comment). However, Hiramatsu et al. [479
] have reported that monocytes from a MPO-deficient patient induced lipid peroxidation of LDL to the same degree as that induced by normal cells. A long-term epidemiological study of the susceptibility of MPO-deficient patients to atherosclerosis would be helpful but difficult to do. However, autopsies of individual MPO-deficient patients may answer the following question: Do MPO-deficient patients in general have cleaner blood vessels than age-controlled, normal individuals?
The presence of MPO in human atherosclerotic lesions raises an additional issue. What is the source of the MPO, and when did it arrive? Is the MPO in atherosclerotic lesions a relic of enzyme deposited there by earlier recruitment of monocytes, is it evidence of the more recent presence of neutrophils or monocytes in the lesion, or is it an indication that mature macrophages can be induced to begin again to synthesize MPO under the conditions prevailing in the atherosclerotic lesion? Progression of atherosclerotic plaques is associated with robust migration of monocytes/macrophages into the lesion and their reduced clearance, leading to the build-up of these cells [480
]. There has been increasing interest in the possibility that atherosclerosis is in part an infectious process as a result of the detection of evidence for Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, or herpes simplex virus 2 infection in atherosclerotic lesions [481
, 482
]. Is MPO brought to the lesion by phagocytes responding to an infectious agent? It is the prevailing view that MPO is synthesized and packaged in the promyelocyte stage of neutrophil development and in the promonocyte in cells of macrophage lineage and that synthesis ceases with further maturation of the cells. Circulating monocytes contain MPO, but as the monocytes mature into macrophages in tissues, this peroxidase is lost. MPO is a strongly cationic protein, which binds to negatively charged particles and cell surfaces and may be taken up by macrophages by pinocytosis or phagocytosis. Thus, the presence of MPO in macrophages doesn’t necessarily indicate its synthesis there. However, the reinstitution of MPO synthesis in mature macrophages in atherosclerotic lesions, possibly under the control of granulocyte macrophage-colony stimulating factor [461
], is an intriguing possibility. Other evidence for the reinstitution of MPO synthesis in mature cells of macrophage lineage has come from studies of brain tissue (see below).
Multiple sclerosis
MPO has been detected in microglia/macrophages in and around the lesions in multiple sclerosis, as measured by the immunocytochemical detection of MPO protein and by the detection of MPO mRNA sequences in brain microglia in this condition, which was not detected in normal brain tissue [483
]. Further, the G allele of the –463G/A MPO polymorphism, which is associated with increased MPO production, is over-represented in early-onset multiple sclerosis in females [483
]. Peripheral blood leukocyte MPO levels have been reported to be decreased in patients with multiple sclerosis [484
]. Experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, developed in 90% of MPO-knockout mice as compared with 33% of wild-type mice, suggesting that MPO is protective to the animal [485
].
Alzheimer’s disease
MPO protein also has been detected by immunohistochemical techniques in microglia adjacent to senile plaques in the cerebral cortex of patients with Alzheimer’s disease [486
]. The MPO colocalized with amyloid ß, and its gene expression could be induced by amyloid ß in cultured rodent microglial cells. APO-E, which colocalizes with amyloid ß in senile plaques of patients with Alzheimer’s disease, is highly susceptible to oxidation by the MPO system [487
, 488
]. MPO has also been detected in increased amounts in certain Alzheimer brain neurons [489
]. Studies relating MPO –463G/A polymorphism to the risk of Alzheimer’s disease have been contradictory. Reynolds et al. [486
] reported that the G allele was over-represented in females, whereas the A allele was overrepresented in males with Alzheimer’s disease. In a subsequent study with a Finnish cohort, the MPO A and the APO-E 
4 alleles were found to synergize to significantly increase the risk of Alzheimer’s disease in men but not in women [490
]. Crawford et al. [491
] detected an association between the MPO G/G genotype and Alzheimer’s disease in a Caucasian but not in a Hispanic population, with no gender association or relationship to the APO-E gene. Leininger-Muller et al. [492
] concluded that the –463G/A MPO polymorphism was statistically associated with Alzheimer’s disease in females but not males, although the low P value led to their conclusion that there was no causal relationship between the MPO genotype and Alzheimer’s disease. In this regard, Combarros et al. [493
] and Styczynska et al. [494
] could not detect an association between the MPO –463G/A genotype and Alzheimer’s disease.
Brain infarction
The A allele of the G –463A polymorphism is associated with a poorer short-term, functional outcome of brain infarcts, and carriers of the A allele of the G –129A polymorphism had significantly larger infarcts. There was no significant relationship between these polymorphisms and the risk of developing a brain infarct [495
].
Parkinson’s disease
Parkinson’s disease is associated with the loss of dopaminergic neurons from the substantia nigra pars compacta area of the brain. NADPH oxidase levels (as measured by the up-regulation of gp91phox and p67phox) are increased in this area of the brain in Parkinson’s disease and in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a model for Parkinson’s disease, and mice deficient in NADPH oxidase have less neuronal loss following MPTP administration than do wild-type mice [496
]. These findings are compatible with a role for NADPH oxidase-derived ROS in the development of the lesions in Parkinson’s disease. The tyrosyl radical generated by MPO and reactive nitrogen species have also been implicated in the brain lesions in mice treated with MPTP [497
]. The presence of MPO in the lesions in certain neurodegenerative diseases and its absence from equivalent normal nervous tissue raise the question of the possible role of MPO in the pathogenesis of these diseases. Studies along the lines of those discussed above in relation to atherosclerosis are needed to resolve this issue.
CONCLUSIONS
The evidence, I believe, strongly suggests that the primary
function of MPO is to kill microorganisms in neutrophils and
monocytes, and to do this, it forms highly reactive halide (particularly
chloride)-derived oxidants in the confines of the phagosome.
Chlorine disinfection is of course not new. In 1827, Thomas
Alcock in an "Essay on the use of Chlorets of Oxide of Sodium
and Lime" recommended the use of what is now called sodium and
calcium hypochlorite as disinfectants. Its most famous early
proponent was Ignaz Philipp Semmelweis, who noted that death
from puerperal fever was considerably higher among women giving
birth in a ward in which medical students and doctors attended
births as compared with a second ward staffed by midwives. He
concluded that the medical students and doctors, who also participated
in autopsies, carried "cadaveric material" on their hands to
the bedside. In May 1847, he posted a sign on the clinic door,
which indicated that any doctor or student coming from the post-mortem
room must wash his hands thoroughly in a basin of chlorinated
water before entering the maternity ward. Shortly thereafter,
the death rate from puerperal fever fell to that observed in
the midwife-run ward. In 1881, Robert Koch demonstrated the
microbicidal effect of hypochlorites on pure cultures of bacteria.
Chlorine-based disinfectants subsequently became widely used
in the treatment of open and infected wounds until the introduction
of the less-toxic antibiotics. Chlorine derivatives, however,
are still widely used in water and sewage treatment and in the
disinfection of laundry, instruments, and swimming pools. By
1990, 98.6% of disinfective practices in the United States used
chlorine-based disinfectants. The body, thus, has found a way
to generate chlorine-based disinfectants in the confines of
the phagosome and in this way, to kill ingested microbes and
control infection.
In conclusion, is MPO a friend or foe? The evidence suggests that MPO is a friend that can, to some degree, be replaced and a foe that has the potential to produce damage and contribute to disease.
Received November 30, 2004;
revised January 7, 2005;
accepted January 9, 2005.
REFERENCES
1 - Klebanoff, S. J. (1959) An effect of thyroxine and related compounds on the oxidation of certain hydrogen donors by the peroxidase system J. Biol. Chem 234,2437-2442[Free Full Text]
2 - Klebanoff, S. J. (1959) An effect of thyroxine on the oxidation of reduced pyridine nucleotides by the peroxidase system J. Biol. Chem 234,2480-2485[Free Full Text]
3 - Morrison, M., Hultquist, D. E. (1963) Lactoperoxidase. II. Isolation J. Biol. Chem 238,2843-2849[Free Full Text]
4 - Agner, K. (1958) Crystalline myeloperoxidase Acta Chem. Scand. A 12,89-94
5 - Klebanoff, S. J., Yip, C., Kessler, D. (1962) The iodination of tyrosine by beef thyroid preparations Biochim. Biophys. Acta 58,563-574[Medline]
6 - Agner, K. (1941) Verdoperoxidase. A ferment isolated from leucocytes Acta Chem. Scand. A 2(Suppl. 8),1-62
7 - Schultz, J., Kaminker, K. (1962) Myeloperoxidase of the leucocyte of normal human blood. 1. Content and localization Arch. Biochem. Biophys 96,465-467[CrossRef][Medline]
8 - Kinkade, J. M., Jr, Pember, S. O., Barnes, K. C., Shapira, R., Spitznagel, J. K., Martin, L. E. (1983) Differential distribution of distinct forms of myeloperoxidase in different azurophilic granule subpopulations from human neutrophils Biochem. Biophys. Res. Commun 114,296-303[CrossRef][Medline]
9 - Bainton, D. F., Ullyot, J. L., Farquhar, M. G. (1971) The development of neutrophilic polymorphonuclear leukocytes in human bone marrow. Origin and content of azurophil and specific granules J. Exp. Med 134,907-934[Abstract]
10 - Nichols, B. A., Bainton, D. F. (1973) Differentiation of human monocytes in bone marrow and blood. Sequential formation of two granule populations Lab. Invest 29,27-40[Medline]
11 - Bainton, D. F., Farquhar, M. G. (1970) Segregation and packaging of granule enzymes in eosinophilic leukocytes J. Cell Biol 45,54-73[Abstract/Free Full Text]
12 - Klebanoff, S. J. (1999) Oxygen metabolites from phagocytes Gallin, J. I. Snyderman, R. eds. Inflammation: Basic Principles and Clinical Correlates ,721-768 Lippincott Williams & Wilkins Philadelphia, PA.
13 - Chang, K. S., Trujillo, J. M., Cook, R. G., Stass, S. A. (1986) Human myeloperoxidase gene: molecular cloning and expression in leukemic cells Blood 68,1411-1414[Abstract/Free Full Text]
14 - Yamada, M., Hur, S-J., Hashinaka, K., Tsuneoka, K., Saeki, T., Nishio, C., Sakiyama, F., Tsunasawa, S. (1987) Isolation and characterization of a cDNA coding for human myeloperoxidase Arch. Biochem. Biophys 255,147-155[CrossRef][Medline]
15 - Morishita, K., Kubota, N., Asano, S., Kaziro, Y., Nagata, S. (1987) Molecular cloning and characterization of cDNA for human myeloperoxidase J. Biol. Chem 262,3844-3851[Abstract/Free Full Text]
16 - Johnson, K. R., Nauseef, W. M., Care, A., Wheelock, M. J., Shane, S., Hudson, S., Koeffler, H. P., Selsted, M., Miller, C., Rovera, G. (1987) Characterization of cDNA clones for human myeloperoxidase: predicted amino acid sequence and evidence for multiple mRNA species Nucleic Acids Res 15,2013-2028[Abstract/Free Full Text]
17 - Weil, S. C., Rosner, G. L., Reid, M. S., Chisholm, R. L., Farber, N. M., Spitznagel, J. K., Swanson, M. S. (1987) cDNA cloning of human myeloperoxidase: decrease in myeloperoxidase mRNA upon induction of HL-60 cells Proc. Natl. Acad. Sci. USA 84,2057-2061[Abstract/Free Full Text]
18 - Venturelli, D., Bittenbender, S., Rovera, G. (1989) Sequence of the murine myeloperoxidase (MPO) gene Nucleic Acids Res 17,7987-7988[Free Full Text]
19 - Hosokawa, Y., Kawaguchi, R., Hikiji, K., Yamada, M., Suzuki, K., Nakagawa, T., Yoshihara, T., Yamaguchi, K. (1993) Cloning and characterization of four types of cDNA encoding myeloperoxidase from human monocytic leukemia cell line, SKM-1 Leukemia 7,441-445[Medline]
20 - Johnson, K. R., Nauseef, W. M. (1991) Molecular biology of MPO Everse, J. Everse, K. E. Grisham, M. B. eds. Peroxidases in Chemistry and Biology I,63-81 CRC Boca Raton, FL.
21 - Chang, K. S., Schroeder, W., Siciliano, M. J., Thompson, L. H., McCredie, K., Beran, M., Freireich, E. J., Liang, J. C., Trujillo, J. M., Stass, S. A. (1987) The localization of the human myeloperoxidase gene is in close proximity to the translocation breakpoint in acute promyelocytic leukemia Leukemia 1,458-462[Medline]
22 - Inazawa, J., Inoue, K., Nishigaki, H., Tsuda, S., Taniwaki, M., Misawa, S., Abe, T. (1989) Assignment of the human myeloperoxidase gene (MPO) to bands q21.3
q23 of chromosome 17 Cytogenet. Cell Genet 50,135-136[Medline]
23 - Zaki, S. R., Austin, G. E., Chan, W. C., Conaty, A. L., Trusler, S., Trappier, S., Lindsey, R. B., Swan, D. C. (1990) Chromosomal localization of the human myeloperoxidase gene by in situ hybridization using oligonucleotide probes Genes Chromosomes Cancer 2,266-270[Medline]
24 - Nauseef, W. M., Olsson, I., Arnljots, K. (1988) Biosynthesis and processing of myeloperoxidase—a marker for myeloid cell differentiation Eur. J. Haematol 40,97-110[Medline]
25 - Stromberg, J., Persson, A-M., Olsson, I. (1986) The processing and intracellular transport of myeloperoxidase. Modulation by lysosomotropic agents and monensin Eur. J. Cell Biol 39,424-431[Medline]
26 - Nauseef, W. M. (1986) Myeloperoxidase biosynthesis by a human promyelocytic leukemia cell line: insight into myeloperoxidase deficiency Blood 67,865-872[Abstract/Free Full Text]
27 - Nauseef, W. M., McCormick, S. J., Clark, R. A. (1995) Calreticulin functions as a molecular chaperone in the biosynthesis of myeloperoxidase J. Biol. Chem 270,4741-4747[Abstract/Free Full Text]
28 - Nauseef, W. M., McCormick, S. J., Goedken, M. (1998) Coordinated participation of calreticulin and calnexin in the biosynthesis of myeloperoxidase J. Biol. Chem 273,7107-7111[Abstract/Free Full Text]
29 - Nauseef, W. M., McCormick, S., Yi, H. (1992) Roles of heme insertion and the mannose-6-phosphate receptor in processing of the human myeloid lysosomal enzyme, myeloperoxidase Blood 80,2622-2633[Abstract/Free Full Text]
30 - Pinnix, I. B., Guzman, G. S., Bonkovsky, H. L., Zaki, S. R., Kinkade, J. M., Jr (1994) The post-translational processing of myeloperoxidase is regulated by the availability of heme Arch. Biochem. Biophys 312,447-458[CrossRef][Medline]
31 - Nauseef, W. M., Cogley, M., McCormick, S. (1996) Effect of the R569W missense mutation on the biosynthesis of myeloperoxidase J. Biol. Chem 271,9546-9549[Abstract/Free Full Text]
32 - Andrews, P. C., Krinsky, N. I. (1981) The reductive cleavage of myeloperoxidase in half, producing enzymatically active hemi-myeloperoxidase J. Biol. Chem 256,4211-4218[Abstract/Free Full Text]
33 - Harrison, J. E., Pabalan, S., Schultz, J. (1977) The subunit structure of crystalline canine myeloperoxidase Biochim. Biophys. Acta 493,247-259[Medline]
34 - Olsen, R. L., Little, C. (1984) Studies on the subunits of human myeloperoxidase Biochem. J 222,701-709[Medline]
35 - Atkin, C. L., Andersen, M. R., Eyre, H. J. (1982) Abnormal neutrophil myeloperoxidase from a patient with chronic myelocytic leukemia Arch. Biochem. Biophys 214,284-292[CrossRef][Medline]
36 - Andrews, P. C., Parnes, C., Krinsky, N. I. (1984) Comparison of myeloperoxidase and hemi-myeloperoxidase with respect to catalysis, regulation, and bactericidal activity Arch. Biochem. Biophys 228,439-442[CrossRef][Medline]
37 - Nauseef, W. M., Malech, H. L. (1986) Analysis of the peptide subunits of human neutrophil myeloperoxidase Blood 67,1504-1507[Abstract/Free Full Text]
38 - Taylor, K. L., Guzman, G. S., Pohl, J., Kinkade, J. M., Jr (1990) Distinct chromatographic forms of human hemi-myeloperoxidase obtained by reductive cleavage of the dimeric enzyme J. Biol. Chem 265,15938-15946[Abstract/Free Full Text]
39 - Fenna, R. E. (1987) Crystallization and subunit structure of canine myeloperoxidase J. Mol. Biol 196,919-925[CrossRef][Medline]
40 - Zeng, J., Fenna, R. E. (1989) Tetragonal crystals of canine myeloperoxidase suitable for X-ray structural analysis J. Mol. Biol 210,681-683[CrossRef][Medline]
41 - Zeng, J., Fenna, R. E. (1992) X-ray crystal structure of canine myeloperoxidase at 3 Å resolution J. Mol. Biol 226,185-207[CrossRef][Medline]
42 - Fenna, R., Zeng, J., Davey, C. (1995) Structure of the green heme in myeloperoxidase Arch. Biochem. Biophys 316,653-656[CrossRef][Medline]
43 - Sutton, B. J., Little, C., Olsen, R. L., Willassen, N. P. (1988) Preliminary crystallographic analysis of human myeloperoxidase J. Mol. Biol 199,395-396[CrossRef][Medline]
44 - Graham, G. S. (1920) The neutrophilic granules of the circulating blood in health and in disease. A preliminary report N. Y. State J. Med 20,46-55
45 - Hirsch, J. G., Cohn, Z. A. (1960) Degranulation of polymorphonuclear leucocytes following phagocytosis of microorganisms J. Exp. Med 112,1005-1014[Abstract]
46 - Cohn, Z. A., Hirsch, J. G. (1960) The isolation and properties of the specific cytoplasmic granules of rabbit polymorphonuclear leukocytes J. Exp. Med 112,1015-1022[Abstract/Free Full Text]
47 - Skarnes, R. C., Watson, D. W. (1956) Characterization of leukin: an antibacterial factor from leucocytes active against gram-positive pathogens J. Exp. Med 104,829-845[Abstract/Free Full Text]
48 - Hirsch, J. G. (1956) Phagocytin: a bactericidal substance from polymorphonuclear leucocytes J. Exp. Med 103,589-611[Abstract]
49 - Klebanoff, S. J. (1970) Myeloperoxidase-mediated antimicrobial systems and their role in leukocyte function Schultz, J. eds. Biochemistry of the Phagocytic Process ,89-110 Amsterdam, North Holland.
50 - Edwards, S. W., Nurcombe, H. L., Hart, C. A. (1987) Oxidative inactivation of myeloperoxidase released from human neutrophils Biochem. J 245,925-928[Medline]
51 - King, C. C., Jefferson, M. M., Thomas, E. L. (1997) Secretion and inactivation of myeloperoxidase by isolated neutrophils J. Leukoc. Biol 61,293-302[Abstract]
52 - Schmekel, B., Hornblad, Y., Linden, M., Sundstrom, C., Venge, P. (1990) Myeloperoxidase in human lung lavage. II. Internalization of myeloperoxidase by alveolar macrophages Inflammation 14,455-461[CrossRef][Medline]
53 - Shepherd, V. L., Hoidal, J. R. (1990) Clearance of neutrophil-derived myeloperoxidase by the macrophage mannose receptor Am. J. Respir. Cell Mol. Biol 2,335-340
54 - Selvaraj, R. J., Zgliczynski, J. M., Sbarra, A. J. (1978) Enhanced killing of myeloperoxidase-coated bacteria in the myeloperoxidase-H2O2-Cl– system J. Infect. Dis 137,481-485[Medline]
55 - Ramsey, P. G., Martin, T., Chi, E., Klebanoff, S. J. (1982) Arming of mononuclear phagocytes by eosinophil peroxidase bound to Staphylococcus aureus. J. Immunol 128,415-420[Abstract]
56 - Noqueira, N. M., Klebanoff, S. J., Cohn, Z. A. (1982) T. cruzi: sensitization to macrophage killing by eosinophil peroxidase J. Immunol 128,1705-1708[Abstract]
57 - Locksley, R. M., Wilson, C. B., Klebanoff, S. J. (1982) Role for endogenous and acquired peroxidase in the toxoplasmacidal activity of murine and human mononuclear phagocytes J. Clin. Invest 69,1099-1111
58 - Sbarra, A. J., Karnovsky, M. L. (1959) The biochemical basis of phagocytosis. 1. Metabolic changes during the ingestion of particles by polymorphonuclear leukocytes J. Biol. Chem 234,1355-1362[Free Full Text]
59 - Sbarra, A. J., Karnovsky, M. L. (1960) The biochemical basis of phagocytosis. 2. Incorporation of C14-labeled building blocks into lipid, protein, and glycogen of leukocytes during phagocytosis J. Biol. Chem 235,2224-2229[Free Full Text]
60 - Baldridge, C. W., Gerard, R. W. (1933) The extra respiration of phagocytosis Am. J. Physiol. 103,235-236
61 - Iyer, G. Y. N., Islam, D. M. F., Quastel, J. H. (1961) Biochemical aspects of phagocytosis Nature 192,535-541[CrossRef]
62 - Kojima, S. (1931) Studies on peroxidase. II. The effect of peroxidase on the bactericidal action of phenols J. Biochem 14,95-109
63 - Zeldow, B. J. (1959) Studies on the antibacterial activity of human saliva. I. A bactericidin for lactobacilli J. Dent. Res 38,798-804[Free Full Text]
64 - Dogon, I. L., Kerr, A. C., Amdur, B. H. (1962) Characterization of an antibacterial factor in human parotid secretions, active against Lactobacillus casei. Arch. Oral Biol 7,81-90[CrossRef][Medline]
65 - Klebanoff, S. J., Luebke, R. G. (1965) The antilactobacillus system of saliva. Role of salivary peroxidase Proc. Soc. Exp. Biol. Med 118,483-486
66 - Klebanoff, S. J., Clem, W. H., Luebke, R. G. (1966) The peroxidase-thiocyanate-hydrogen peroxide antimicrobial system Biochim. Biophys. Acta 117,63-72[Medline]
67 - Reiter, B., Pickering, A., Oram, J. D. (1964) An inhibitory system—lactoperoxidase/thiocyanate/peroxide—in raw milk 4th Inernationaional Symposium on Food Microbiology SIK ,297-305 Goteborg, Sweden.
68 - Klebanoff, S. J. (1967) A peroxidase-mediated antimicrobial system in leukocytes J. Clin. Invest 46,1078A
69 - Klebanoff, S. J. (1967) Iodination of bacteria: a bactericidal mechanism J. Exp. Med 126,1063-1078[Abstract]
70 - Klebanoff, S. J. (1968) Myeloperoxidase-halide-hydrogen peroxide antibacterial system J. Bacteriol 95,2131-2138[Abstract/Free Full Text]
71 - Klebanoff, S. J. (1999) Myeloperoxidase Proc. Assoc. Am. Physicians 111,383-389[Medline]
72 - McRipley, R. J., Sbarra, A. J. (1967) Role of the phagocyte in host-parasite interactions. XII. Hydrogen peroxide-myeloperoxidase bactericidal system in the phagocyte J. Bacteriol 94,1425-1430[Abstract/Free Full Text]
73 - Paul, B. B., Jacob, A. A., Strauss, R. R., Sbarra, A. J. (1970) Role of the phagocyte in host-parasite interactions. XXIV. Aldehyde formation by the myeloperoxidase-H2O2-chloride anti-microbial system: A possible in vivo mechanism of action Infect. Immun 2,414-418[Abstract/Free Full Text]
74 - Rossi, F., Zatti, M. (1964) Biochemical aspects of phagocytosis in polymorphonuclear leucocytes. NADH and NADPH oxidation by the granules of resting and phagocytizing cells Experientia 20,21-23[CrossRef][Medline]
75 - Babior, B. M., Kipnes, R. S., Curnutte, J. T. (1973) Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent J. Clin. Invest 52,741-744
76 - Babior, B. M., Lambeth, J. D., Nauseef, W. (2002) The neutrophil NADPH oxidase Arch. Biochem. Biophys 397,342-344[CrossRef][Medline]
77 - Babior, B. M. (2004) NADPH oxidase Curr. Opin. Immunol 16,42-47[CrossRef][Medline]
78 - Roos, D., van Bruggen, R., Meischl, C. (2003) Oxidative killing of microbes by neutrophils Microbes Infect 5,1307-1315[CrossRef][Medline]
79 - Quinn, M. T., Gauss, K. A. (2004) Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases J. Leukoc. Biol 76,760-781[Abstract/Free Full Text]
80 - Bromberg, Y., Pick, E. (1984) Unsaturated fatty acids stimulate NADPH-dependent superoxide production by cell-free system derived from macrophages Cell. Immunol 88,213-221[CrossRef][Medline]
81 - Heyneman, R. A., Vercauteren, R. E. (1984) Activation of a NADPH oxidase from horse polymorphonuclear leukocytes in a cell-free system J. Leukoc. Biol 36,751-759[Abstract]
82 - Bromberg, Y., Pick, E. (1985) Activation of NADPH-dependent superoxide production in a cell-free system by sodium dodecyl sulfate J. Biol. Chem 260,13539-13545[Abstract/Free Full Text]
83 - Segal, A. W., Jones, O. T. (1978) Novel cytochrome b system in phagocytic vacuoles of human granulocytes Nature 276,515-517[CrossRef][Medline]
84 - Segal, A. W., Garcia, R., Goldstone, A. H., Cross, A. R., Jones, O. T. G. (1981) Cytochrome b–245 of neutrophils is also present in human monocytes, macrophages and eosinophils Biochem. J 196,363-367[Medline]
85 - Royer-Pokora, B., Kunkel, L. M., Monaco, A. P., Goff, S. C., Newburger, P. E., Baehner, R. L., Cole, F. S., Curnutte, J. T., Orkin, S. H. (1986) Cloning the gene for an inherited human disorder–chronic granulomatous disease–on the basis of its chromosomal location Nature 322,32-38[CrossRef][Medline]
86 - Orkin, S. H. (1986) Reverse genetics and human disease Cell 47,845-850[CrossRef][Medline]
87 - Abo, A., Pick, E., Hall, A., Totty, N., Teahan, C. G., Segal, A. W. (1991) Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1 Nature 353,668-670[CrossRef][Medline]
88 - Knaus, U. G., Heyworth, P. G., Evans, T., Curnutte, J. T., Bokoch, G. M. (1991) Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2 Science 254,1512-1515[Abstract/Free Full Text]
89 - Heyworth, P. G., Bohl, B. P., Bokoch, G. M., Curnutte, J. T. (1994) Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its interaction with flavocytochrome b558 J. Biol. Chem 269,30749-30752[Abstract/Free Full Text]
90 - Volpp, B. D., Nauseef, W. M., Clark, R. A. (1988) Two cytosolic neutrophil oxidase components absent in autosomal chronic granulomatous disease Science 242,1295-1297[Abstract/Free Full Text]
91 - Volpp, B. D., Nauseef, W. M., Donelson, J. E., Moser, D. R., Clark, R. A. (1989) Cloning of the cDNA and functional expression of the 47-kilodalton cytosolic component of human neutrophil respiratory burst oxidase Proc. Natl. Acad. Sci. USA 86,7195-7199[Abstract/Free Full Text]
92 - Leto, T. L., Lomax, K. J., Volpp, B. D., Nunoi, H., Sechler, J. M., Nauseef, W. M., Clark, R. A., Gallin, J. I., Malech, H. L. (1990) Cloning of a 67-kD neutrophil oxidase factor with similarity to a noncatalytic region of p60c-src Science 248,727-730[Abstract/Free Full Text]
93 - Bokoch, G. M., Diebold, B. A. (2002) Current molecular models for NADPH oxidase regulation by Rac GTPase Blood 100,2692-2696[Abstract/Free Full Text]
94 - Quie, P. G., White, J. G., Holmes, B., Good, R. A. (1967) In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood J. Clin. Invest 46,668-679
95 - Berendes, H., Bridges, R. A., Good, R. A. (1957) A fatal granulomatosus of childhood: the clinical study of a new syndrome Minn. Med 40,309-312[Medline]
96 - Holmes, B., Page, A. R., Good, R. A. (1967) Studies of the metabolic activity of leukocytes from patients with a genetic abnormality of phagocytic function J. Clin. Invest 46,1422-1432
97 - Segal, B. H., Leto, T. L., Gallin, J. I., Malech, H. L., Holland, S. M. (2000) Genetic, biochemical, and clinical features of chronic granulomatous disease Medicine (Baltimore) 79,170-200[CrossRef][Medline]
98 - Heyworth, P. G., Cross, A. R., Curnutte, J. T. (2003) Chronic granulomatous disease Curr. Opin. Immunol 15,578-584[CrossRef][Medline]
99 - Segal, A. W., Jones, O. T., Webster, D., Allison, A. C. (1978) Absence of a newly described cytochrome b from neutrophils of patients with chronic granulomatous disease Lancet 2,446-449[Medline]
100 - Dinauer, M. C., Curnutte, J. T., Rosen, H., Orkin, S. H. (1989) A missense mutation in the neutrophil cytochrome b heavy chain in cytochrome-positive X-linked chronic granulomatous disease J. Clin. Invest 84,2012-2016
101 - Nunoi, H., Rotrosen, D., Gallin, J. I., Malech, H. L. (1988) Two forms of autosomal chronic granulomatous disease lack distinct neutrophil cytosol factors Science 242,1298-1301[Abstract/Free Full Text]
102 - Ambruso, D. R., Knall, C., Abell, A. N., Panepinto, J., Kurkchubasche, A., Thurman, G., Gonzalez-Aller, C., Hiester, A., deBoer, M., Harbeck, R. J., Oyer, R., Johnson, G. L., Roos, D. (2000) Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation Proc. Natl. Acad. Sci. USA 97,4654-4659[Abstract/Free Full Text]
103 - Williams, D. A., Tao, W., Yang, F., Kim, C., Gu, Y., Mansfield, P., Levine, J. E., Petryniak, B., Derrow, C. W., Harris, C., Jia, B., Zheng, Y., Ambruso, D. R., Lowe, J. B., Atkinson, S. J., Dinauer, M. C., Boxer, L. (2000) Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency Blood 96,1646-1654[Abstract/Free Full Text]
104 - Kurkchubasche, A. G., Panepinto, J. A., Tracy, T. F., Jr, Thurman, G. W., Ambruso, D. R. (2001) Clinical features of a human Rac2 mutation: a complex neutrophil dysfunction disease J. Pediatr 139,141-147[CrossRef][Medline]
105 - Warnholtz, A., Nickenig, G., Schulz, E., Macharzina, R., Brasen, J. H., Skatchkov, M., Heitzer, T., Stasch, J. P., Griendling, K. K., Harrison, D. G., Bohm, M., Meinertz, T., Munzel, T. (1999) Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system Circulation 99,2027-2033[Abstract/Free Full Text]
106 - Yokoyama, M., Inoue, N., Kawashima, S. (2000) Role of the vascular NADH/NADPH oxidase system in atherosclerosis Ann. N. Y. Acad. Sci 902,241-247[Medline]
107 - Griendling, K. K., Sorescu, D., Ushio-Fukai, M. (2000) NAD(P)H oxidase: role in cardiovascular biology and disease Circ. Res 86,494-501[Abstract/Free Full Text]
108 - Sorescu, D., Szocs, K., Griendling, K. K. (2001) NAD(P)H oxidases and their relevance to atherosclerosis Trends Cardiovasc. Med 11,124-131[CrossRef][Medline]
109 - Souza, H. P., Laurindo, F. R., Ziegelstein, R. C., Berlowitz, C. O., Zweier, J. L. (2001) Vascular NAD(P)H oxidase is distinct from the phagocytic enzyme and modulates vascular reactivity control Am. J. Physiol. Heart Circ. Physiol 280,H658-H667[Abstract/Free Full Text]
110 - Zhang, C., Yang, J., Jacobs, J. D., Jennings, L. K. (2003) Interaction of myeloperoxidase with vascular NAD(P)H oxidase-derived reactive oxygen species in vasculature: implications for vascular diseases Am. J. Physiol. Heart Circ. Physiol 285,H2563-H2572[Abstract/Free Full Text]
111 - Eiserich, J. P., Baldus, S., Brennan, M. L., Ma, W., Zhang, C., Tousson, A., Castro, L., Lusis, A. J., Nauseef, W. M., White, C. R., Freeman, B. A. (2002) Myeloperoxidase, a leukocyte-derived vascular NO oxidase Science 296,2391-2394[Abstract/Free Full Text]
112 - Bokoch, G. M., Knaus, U. G. (2003) NADPH oxidases: not just for leukocytes anymore! Trends Biochem. Sci 28,502-508[CrossRef][Medline]
113 - Lambeth, J. D. (2004) NOX enzymes and the biology of reactive oxygen Nat. Rev. Immunol 4,181-189[CrossRef][Medline]
114 - Suh, Y. A., Arnold, R. S., Lassegue, B., Shi, J., Xu, X., Sorescu, D., Chung, A. B., Griendling, K. K., Lambeth, J. D. (1999) Cell transformation by the superoxide-generating oxidase Mox1 Nature 401,79-82[CrossRef][Medline]
115 - Shiose, A., Kuroda, J., Tsuruya, K., Hirai, M., Hirakata, H., Naito, S., Hattori, M., Sakaki, Y., Sumimoto, H. (2001) A novel superoxide-producing NAD(P)H oxidase in kidney J. Biol. Chem 276,1417-1423[Abstract/Free Full Text]
116 - Dupuy, C., Ohayon, R., Valent, A., Noel-Hudson, M. S., Deme, D., Virion, A. (1999) Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cdnas J. Biol. Chem 274,37265-37269[Abstract/Free Full Text]
117 - De Deken, X., Wang, D., Many, M. C., Costagliola, S., Libert, F., Vassart, G., Dumont, J. E., Miot, F. (2000) Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family J. Biol. Chem 275,23227-23233[Abstract/Free Full Text]
118 - Banfi, B., Molnar, G., Maturana, A., Steger, K., Hegedus, B., Demaurex, N., Krause, K. H. (2001) A Ca(2+)-activated NADPH oxidase in testis, spleen, and lymph nodes J. Biol. Chem 276,37594-37601[Abstract/Free Full Text]
119 - Geiszt, M., Kopp, J. B., Varnai, P., Leto, T. L. (2000) Identification of renox, an NAD(P)H oxidase in kidney Proc. Natl. Acad. Sci. USA 97,8010-8014[Abstract/Free Full Text]
120 - Banfi, B., Clark, R. A., Steger, K., Krause, K. H. (2003) Two novel proteins activate superoxide generation by the NADPH oxidase NOX1 J. Biol. Chem 278,3510-3513[Abstract/Free Full Text]
121 - Edens, W. A., Sharling, L., Cheng, G., Shapira, R., Kinkade, J. M., Lee, T., Edens, H. A., Tang, X., Sullards, C., Flaherty, D. B., Benian, G. M., Lambeth, J. D. (2001) Tyrosine cross-linking of extracellular matrix is catalyzed by Duox, a multidomain oxidase/peroxidase with homology to the phagocyte oxidase subunit gp91phox J. Cell Biol 154,879-891[Abstract/Free Full Text]
122 - Takeya, R., Ueno, N., Kami, K., Taura, M., Kohjima, M., Izaki, T., Nunoi, H., Sumimoto, H. (2003) Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases J. Biol. Chem 278,25234-25246[Abstract/Free Full Text]
123 - Cheng, G., Lambeth, J. D. (2004) NOXO1, regulation of lipid binding, localization, and activation of Nox1 by the Phox homology (PX) domain J. Biol. Chem 279,4737-4742[Abstract/Free Full Text]
124 - Banfi, B., Tirone, F., Durussel, I., Knisz, J., Moskwa, P., Molnar, G. Z., Krause, K. H., Cox, J. A. (2004) Mechanism of Ca2+ activation of the NADPH oxidase NOX5 J. Biol. Chem. 279,18583-18591[Abstract/Free Full Text]
125 - De Deken, X., Wang, D., Dumont, J. E., Miot, F. (2002) Characterization of ThOX proteins as components of the thyroid H(2)O(2)-generating system Exp. Cell Res 273,187-196[CrossRef][Medline]
126 - Moreno, J. C., Bikker, H., Kempers, M. J., van Trotsenburg, A. S., Baas, F., de Vijlder, J. J., Vulsma, T., Ris-Stalpers, C. (2002) Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism N. Engl. J. Med 347,95-102[Abstract/Free Full Text]
127 - Geiszt, M., Witta, J., Baffi, J., Lekstrom, K., Leto, T. L. (2003) Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense FASEB J 17,1502-1504[Abstract/Free Full Text]
128 - Granger, D. N., Rutili, G., McCord, J. M. (1981) Superoxide radicals in feline intestinal ischemia Gastroenterology 81,22-29[Medline]
129 - Whittenbury, R. (1964) Hydrogen peroxide formation and catalase activity in the lactic acid bacteria J. Gen. Microbiol 35,13-26[Abstract/Free Full Text]
130 - Eschenbach, D. A., Davick, P. R., Williams, B. L., Klebanoff, S. J., Young-Smith, K., Critchlow, C. M., Holmes, K. K. (1989) Prevalence of hydrogen peroxide-producing Lactobacillus species in normal women and women with bacterial vaginosis J. Clin. Microbiol 27,251-256[Abstract/Free Full Text]
131 - Gupta, K., Stapleton, A. E., Hooton, T. M., Roberts, P. L., Fennell, C. L., Stamm, W. E. (1998) Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections J. Infect. Dis 178,446-450[Medline]
132 - Klebanoff, S. J., Hillier, S. L., Eschenbach, D. A., Waltersdorph, A. W. (1991) Control of the microbial flora of the vagina by H2O2-generating lactobacilli J. Infect. Dis 164,94-100[Medline]
133 - Klebanoff, S. J. (1992) Effects of the spermicidal agent nonoxynol-9 on vaginal microbial flora J. Infect. Dis 165,19-25[Medline]
134 - Klebanoff, S. J., Coombs, R. W. (1991) Viricidal effect of Lactobacillus acidophilus on human immunodeficiency virus type 1: possible role in heterosexual transmission J. Exp. Med 174,289-292[Abstract/Free Full Text]
135 - Herzberg, M., Joel, C. A., Katchalsky, A. (1964) The cyclic variation of sodium chloride content in the mucus of the cervix uteri Fertil. Steril 15,684-694[Medline]
136 - Hooton, T. M., Klebanoff, S. J. (1993) Association of urogenital infections with spermicides Infect. Med 10,40-47
137 - Hooton, T. M., Hillier, S., Johnson, C., Roberts, P. L., Stamm, W. E. (1991) Escherichia coli bacteriuria and contraceptive method JAMA 265,64-69[Abstract/Free Full Text]
138 - McGroarty, J. A., Chong, S., Reid, G., Bruce, A. W. (1990) Influence of the spermicidal compound nonoxynol-9 on the growth and adhesion of urogenital bacteria in vitro Curr. Microbiol 21,219-223[CrossRef]
139 - Agner, K. (1958) Peroxidative oxidation of chloride ions Proceedings of the 4th International Congress on Biochemistry 15,64A Vienna.
140 - Agner, K. (1972) Biological effects of hypochlorous acid formed by "MPO"-peroxidation in the presence of chloride ions Akeson, A. Ehrenberg, A. eds. Structure and Function of Oxidation Reduction Enzymes 18,329-335 Pergamon New York, NY.
141 - Harrison, J. E., Schultz, J. (1976) Studies on the chlorinating activity of myeloperoxidase J. Biol. Chem 251,1371-1374[Abstract/Free Full Text]
142 - Odajima, T., Yamazaki, I. (1970) Myeloperoxidase of the leukocyte of normal blood. I. Reaction of myeloperoxidase with hydrogen peroxide Biochim. Biophys. Acta 206,71-77[Medline]
143 - Marquez, L. A., Huang, J. T., Dunford, H. B. (1994) Spectral and kinetic studies on the formation of myeloperoxidase compounds I and II: roles of hydrogen peroxide and superoxide Biochemistry 33,1447-1454[CrossRef][Medline]
144 - Furtmuller, P. G., Burner, U., Jantschko, W., Regelsberger, G., Obinger, C. (2000) The reactivity of myeloperoxidase compound I formed with hypochlorous acid Redox Rep 5,173-178[CrossRef][Medline]
145 - Harrison, J. E. (1976) The functional mechanism of myeloperoxidase Schultz, J. Ahmad, F. eds. Cancer Enzymology ,305-317 Academic New York, NY.
146 - Kettle, A. J., Winterbourn, C. C. (1988) Superoxide modulates the activity of myeloperoxidase and optimizes the production of hypochlorous acid Biochem. J 252,529-536[Medline]
147 - Kettle, A. J., Winterbourn, C. C. (1989) Influence of superoxide on myeloperoxidase kinetics measured with a hydrogen peroxide electrode Biochem. J 263,823-828[Medline]
148 - Kettle, A. J., Winterbourn, C. C. (1990) Superoxide enhances hypochlorous acid production by stimulated human neutrophils Biochim. Biophys. Acta 1052,379-385[Medline]
149 - Bolscher, B. G. J. M., Zoutberg, G. R., Cuperus, R. A., Wever, R. (1984) Vitamin C stimulates the chlorinating activity of human myeloperoxidase Biochim. Biophys. Acta 784,189-191[CrossRef][Medline]
150 - Marquez, L. A., Dunford, H. B., Van Wart, H. (1990) Kinetic studies on the reaction of compound II of myeloperoxidase with ascorbic acid. Role of ascorbic acid in myeloperoxidase function J. Biol. Chem 265,5666-5670[Abstract/Free Full Text]
151 - Kettle, A. J., Winterbourn, C. C. (1991) The influence of superoxide on the production of hypochlorous acid by human neutrophils Free Radic. Res. Commun 12-13,47-52
152 - Marquez, L. A., Dunford, H. B. (1990) Reaction of compound III of myeloperoxidase with ascorbic acid J. Biol. Chem 265,6074-6078[Abstract/Free Full Text]
153 - Odajima, T., Yamazaki, I. (1972) Myeloperoxidase of the leukocyte of normal blood. III. The reaction of ferric myeloperoxidase with superoxide anion Biochim. Biophys. Acta 284,355-359[Medline]
154 - Winterbourn, C. C., Garcia, R. C., Segal, A. W. (1985) Production of the superoxide adduct of myeloperoxidase (compound III) by stimulated human neutrophils and its reactivity with hydrogen peroxide and chloride Biochem. J 228,583-592[Medline]
155 - Metodiewa, D., Dunford, H. B. (1989) The reactions of horseradish peroxidase, lactoperoxidase, and myeloperoxidase with enzymatically generated superoxide Arch. Biochem. Biophys 272,245-253[CrossRef][Medline]
156 - Kettle, A. J., Sangster, D. F., Gebicki, J. M., Winterbourn, C. C. (1988) A pulse radiolysis investigation of the reactions of myeloperoxidase with superoxide and hydrogen peroxide Biochim. Biophys. Acta 956,58-62[CrossRef][Medline]
157 - Wittenberg, J. B., Noble, R. W., Wittenberg, B. A., Antonini, E., Brunori, M., Wyman, J. (1967) Studies on the equilibria and kinetics of the reactions of peroxidase with ligands. II. The reaction of ferroperoxidase with oxygen J. Biol. Chem 242,626-634[Abstract/Free Full Text]
158 - Yamazaki, I., Yokota, K. N. (1973) Oxidation states of peroxidase Mol. Cell. Biochem 2,39-52[CrossRef][Medline]
159 - Phelps, C. F., Antonini, E., Giacometti, G., Brunori, M. (1974) The kinetics of oxidation of ferroperoxidase by molecular oxygen Biochem. J 141,265-272[Medline]
160 - Tamura, M., Yamazaki, I. (1972) Reactions of the oxyform of horseradish peroxidase J. Biochem., (Tokyo) 71,311-319[Abstract/Free Full Text]
161 - Yokota, K., Yamazaki, I. (1965) Reaction of peroxidase with reduced nicotinamide-adenine dinucleotide and reduced nicotinamide-adenine dinucleotide phosphate Biochim. Biophys. Acta 105,301-312[Medline]
162 - Yokota, K., Yamazaki, I. (1965) The activity of the horseradish peroxidase compound III Biochem. Biophys. Res. Commun 18,48-53[CrossRef][Medline]
163 - Hazen, S. L., Hsu, F. F., Mueller, D. M., Crowley, J. R., Heinecke, J. W. (1996) Human neutrophils employ chlorine gas as an oxidant during phagocytosis J. Clin. Invest 98,1283-1289[Medline]
164 - Hazen, S. L., Hsu, F. F., Duffin, K., Heinecke, J. W. (1996) Molecular chlorine generated by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes converts low density lipoprotein cholesterol into a family of chlorinated sterols J. Biol. Chem 271,23080-23088[Abstract/Free Full Text]
165 - Henderson, J. P., Byun, J., Heinecke, J. W. (1999) Molecular chlorine generated by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes produces 5-chlorocytosine in bacterial RNA J. Biol. Chem 274,33440-33448[Abstract/Free Full Text]
166 - Winterbourn, C. C. (2002) Biological reactivity and biomarkers of the neutrophil oxidant, hypochlorous acid Toxicology 181–182,223-227
167 - Albrich, J. M., Gilbaugh, J. H. I., Callahan, K. B., Hurst, J. K. (1986) Effects of the putative neutrophil-generating toxin, hypochlorous acid, on membrane permeability and transport systems of Escherichia coli. J. Clin. Invest 78,177-184
168 - Rakita, R. M., Michel, B. R., Rosen, H. (1990) Differential inactivation of Escherichia coli membrane dehydrogenases by a myeloperoxidase-mediated antimicrobial system Biochemistry 29,1075-1080[CrossRef][Medline]
169 - Barrette, W. C., Jr, Albrich, J. M., Hurst, J. K. (1987) Hypochlorous acid-promoted loss of metabolic energy in Escherichia coli. Infect. Immun 55,2518-2525[Abstract/Free Full Text]
170 - Rosen, H., Orman, J., Rakita, R. M., Michel, B. R., VanDevanter, D. R. (1990) Loss of DNA-membrane interactions and cessation of DNA synthesis in myeloperoxidase-treated Escherichia coli. Proc. Natl. Acad. Sci. USA 87,10048-10052[Abstract/Free Full Text]
171 - Hazen, S. L., d’Avignon, A., Anderson, M. M., Hsu, F. F., Heinecke, J. W. (1998) Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to oxidize -amino acids to a family of reactive aldehydes. Mechanistic studies identifying labile intermediates along the reaction pathway J. Biol. Chem 273,4997-5005[Abstract/Free Full Text]
172 - Hazen, S. L., Hsu, F. F., d’Avignon, A., Heinecke, J. W. (1998) Human neutrophils employ myeloperoxidase to convert -amino acids to a battery of reactive aldehydes: a pathway for aldehyde generation at sites of inflammation Biochemistry 37,6864-6873[CrossRef][Medline]
173 - Soupart, P. (1962) Free amino acids in blood and urine in the human Holden, J. T. eds. Amino Acid Pools ,220-262 Elsevier Amsterdam.
174 - Learn, D. B., Fried, V. A., Thomas, E. L. (1990) Taurine and hypotaurine content of human leukocytes J. Leukoc. Biol 48,174-182[Abstract]
175 - Schuller-Levis, G. B., Park, E. (2003) Taurine: new implications for an old amino acid FEMS Microbiol. Lett 226,195-202[CrossRef][Medline]
176 - Peskin, A. V., Winterbourn, C. C. (2003) Histamine chloramine reactivity with thiol compounds, ascorbate, and methionine and with intracellular glutathione Free Radic. Biol. Med 35,1252-1260[CrossRef][Medline]
177 - Domigan, N. M., Charlton, T. S., Duncan, M. W., Winterbourn, C. C., Kettle, A. J. (1995) Chlorination of tyrosyl residues in peptides by myeloperoxidase and human neutrophils J. Biol. Chem 270,16542-16548[Abstract/Free Full Text]
178 - Heinecke, J. W., Li, W., Daehnke, H. L., III, Goldstein, J. A. (1993) Dityrosine, a specific marker of oxidation, is synthesized by the myeloperoxidase-hydrogen peroxide system of human neutrophils and macrophages J. Biol. Chem 268,4069-4077[Abstract/Free Full Text]
179 - Savenkova, M. I., Mueller, D. M., Heinecke, J. W. (1994) Tyrosyl radical generated by myeloperoxidase is a physiological catalyst for the initiation of lipid peroxidation in low density lipoprotein J. Biol. Chem 269,20394-20400[Abstract/Free Full Text]
180 - Jacob, J. S., Cistola, D. P., Hsu, F. F., Muzaffar, S., Mueller, D. M., Hazen, S. L., Heinecke, J. W. (1996) Human phagocytes employ the myeloperoxidase-hydrogen peroxide system to synthesize dityrosine trityrosine, pulcherosine, and isodityrosine by a tyrosyl radical-dependent pathway J. Biol. Chem 271,19950-19956[Abstract/Free Full Text]
181 - Heinecke, J. W., Li, W., Francis, G. A., Goldstein, J. A. (1993) Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins J. Clin. Invest 91,2866-2872
182 - Winterbourn, C. C., Pichorner, H., Kettle, A. J. (1997) Myeloperoxidase-dependent generation of a tyrosine peroxide by neutrophils Arch. Biochem. Biophys 338,15-21[CrossRef][Medline]
183 - Fenton, H. J. H. (1894) Oxidation of tartaric acid in the presence of iron J. Chem. Soc 65,899-910
184 - Haber, F., Weiss, J. (1934) The catalytic decomposition of hydrogen peroxide by iron salts Proc. R. Soc. Lond. A 147,332-351[Free Full Text]
185 - Ramos, C. L., Pou, S., Britigan, B. E., Cohen, M. S., Rosen, G. M. (1992) Spin trapping evidence for myeloperoxidase-dependent hydroxyl radical formation by human neutrophils and monocytes J. Biol. Chem 267,8307-8312[Abstract/Free Full Text]
186 - Lymar, S. V., Hurst, J. K. (1995) Role of compartmentation in promoting toxicity of leukocyte-generated strong oxidants Chem. Res. Toxicol 8,833-840[CrossRef][Medline]
187 - Foote, C. S., Abakerli, R. B., Clough, R. L., Lehrer, R. I. (1980) On the question of singlet oxygen production in polymorphonuclear leucocytes DeLuca, M. A. McElroy, W. D. eds. Bioluminescence and Chemiluminescence ,81-88 Academic New York, NY.
188 - Foote, C. S., Abakerli, R. B., Clough, R. L., Shook, F. C. (1980) On the question of singlet oxygen production in leukocytes, macrophages and the dismutation of superoxide anion Dev. Biochem 11B,222-230
189 - Kanofsky, J. R., Wright, J., Miles-Richardson, G. E., Tauber, A. I. (1984) Biochemical requirement for singlet oxygen production by purified human myeloperoxidase J. Clin. Invest 74,1489-1495
190 - Kanofsky, J. R., Tauber, A. I. (1983) Non-physiologic production of singlet oxygen by human neutrophils and by the myeloperoxidase-H2O2-halide system Blood 62,82a
191 - Steinbeck, M. J., Khan, A. U., Karnovsky, M. J. (1992) Intracellular singlet oxygen generation by phagocytosing neutrophils in response to particles coated with a chemical trap J. Biol. Chem 267,13425-13433[Abstract/Free Full Text]
192 - Arisawa, F., Tatsuzawa, H., Kambayashi, Y., Kuwano, H., Fujimori, K., Nakano, M. (2003) MCLA-dependent chemiluminescence suggests that singlet oxygen plays a pivotal role in myeloperoxidase-catalyzed bactericidal action in neutrophil phagosomes Luminescence 18,229-238[CrossRef][Medline]
193 - Kiryu, C., Makiuchi, M., Miyazaki, J., Fujinaga, T., Kakinuma, K. (1999) Physiological production of singlet molecular oxygen in the myeloperoxidase-H2O2-chloride system FEBS Lett 443,154-158[CrossRef][Medline]
194 - Wentworth, A. D., Jones, L. H., Wentworth, P., Jr, Janda, K. D., Lerner, R. A. (2000) Antibodies have the intrinsic capacity to destroy antigens Proc. Natl. Acad. Sci. USA 97,10930-10935[Abstract/Free Full Text]
195 - Wentworth, P., Jr, Jones, L. H., Wentworth, A. D., Zhu, X., Larsen, N. A., Wilson, I. A., Xu, X., Goddard, W. A., III, Janda, K. D., Eschenmoser, A., Lerner, R. A. (2001) Antibody catalysis of the oxidation of water Science 293,1806-1811[Abstract/Free Full Text]
196 - Wentworth, P., Jr, McDunn, J. E., Wentworth, A. D., Takeuchi, C., Nieva, J., Jones, T., Bautista, C., Ruedi, J. M., Gutierrez, A., Janda, K. D., Babior, B. M., Eschenmoser, A., Lerner, R. A. (2002) Evidence for antibody-catalyzed ozone formation in bacterial killing and inflammation Science 298,2195-2199[Abstract/Free Full Text]
197 - Wentworth, P., Jr, Wentworth, A. D., Zhu, X., Wilson, I. A., Janda, K. D., Eschenmoser, A., Lerner, R. A. (2003) Evidence for the production of trioxygen species during antibody-catalyzed chemical modification of antigens Proc. Natl. Acad. Sci. USA 100,1490-1493[Abstract/Free Full Text]
198 - Babior, B. M., Takeuchi, C., Ruedi, J., Gutierrez, A., Wentworth, P., Jr (2003) Investigating antibody-catalyzed ozone generation by human neutrophils Proc. Natl. Acad. Sci. USA 100,3031-3034[Abstract/Free Full Text]
199 - Kettle, A. J., Clark, B. M., Winterbourn, C. C. (2004) Superoxide converts indigo carmine to isatin sulfonic acid: implications for the hypothesis that neutrophils produce ozone J. Biol. Chem 279,18521-18525[Abstract/Free Full Text]
200 - Hampton, M. B., Kettle, A. J., Winterbourn, C. C. (1998) Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing Blood 92,3007-3017[Free Full Text]
201 - Winterbourn, C. C., Vissers, M. C., Kettle, A. J. (2000) Myeloperoxidase Curr. Opin. Hematol 7,53-58[CrossRef][Medline]
202 - Klebanoff, S. J. (1993) Reactive nitrogen intermediates and antimicrobial activity: role of nitrite Free Radic. Biol. Med 14,351-360[CrossRef][Medline]
203 - Gaut, J. P., Byun, J., Tran, H. D., Lauber, W. M., Carroll, J. A., Hotchkiss, R. S., Belaaouaj, A., Heinecke, J. W. (2002) Myeloperoxidase produces nitrating oxidants in vivo J. Clin. Invest 109,1311-1319[CrossRef][Medline]
204 - Klebanoff, S. J., Green, W. L. (1973) Degradation of thyroid hormones by phagocytosing human leukocytes J. Clin. Invest 52,60-72
205 - Woeber, K. A., Ingbar, S. H. (1973) Metabolism of L-thyroxine by phagocytosing human leukocytes J. Clin. Invest 52,1796-1803
206 - Thomas, E. L., Fishman, M. (1986) Oxidation of chloride and thiocyanate by isolated leukocytes J. Biol. Chem 261,9694-9702[Abstract/Free Full Text]
207 - Gaut, J. P., Yeh, G. C., Tran, H. D., Byun, J., Henderson, J. P., Richter, G. M., Brennan, M. L., Lusis, A. J., Belaaouaj, A., Hotchkiss, R. S., Heinecke, J. W. (2001) Neutrophils employ the myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis Proc. Natl. Acad. Sci. USA 98,11961-11966[Abstract/Free Full Text]
208 - van Dalen, C. J., Whitehouse, M. W., Winterbourn, C. C., Kettle, A. J. (1997) Thiocyanate and chloride as competing substrates for myeloperoxidase Biochem. J 327,487-492
209 - Furtmuller, P. G., Burner, U., Obinger, C. (1998) Reaction of myeloperoxidase compound I with chloride, bromide, iodide, and thiocyanate Biochemistry 37,17923-17930[CrossRef][Medline]
210 - Briggs, R. T., Karnovsky, M. L., Karnovsky, M. J. (1975) Cytochemical demonstration of hydrogen peroxide in the polymorphonuclear leukocyte phagosomes J. Cell Biol 64,254-260[Abstract/Free Full Text]
211 - Briggs, R. T., Drath, D. B., Karnovsky, M. L., Karnovsky, M. J. (1975) Localization of NADH oxidase on the surface of human polymorphonuclear leukocytes by a new cytochemical method J. Cell Biol 67,566-586[Abstract/Free Full Text]
212 - Briggs, R. T., Robinson, J. M., Karnovsky, M. L., Karnovsky, M. J. (1986) Superoxide production by polymorphonuclear leukocytes. A cytochemical approach Histochemistry 84,371-378[CrossRef][Medline]
213 - Foote, C. S., Goyne, T. E., Lehrer, R. I. (1983) Assessment of chlorination by human neutrophils Nature 301,715-716[CrossRef][Medline]
214 - Thomas, E. L., Grisham, M. B., Jefferson, M. M. (1983) Myeloperoxidase-dependent effect of amines on functions of isolated neutrophils J. Clin. Invest 72,441-454
215 - Weiss, S. J., Klein, R., Slivka, A., Wei, M. (1982) Chlorination of taurine by human neutrophils. Evidence for hypochlorous acid generation J. Clin. Invest 70,598-607
216 - Jiang, Q., Griffin, D. A., Barofsky, D. F., Hurst, J. K. (1997) Intraphagosomal chlorination dynamics and yields determined using unique fluorescent bacterial mimics Chem. Res. Toxicol 10,1080-1089[CrossRef][Medline]
217 - Griffin, F. M., Jr, Griffin, J. A., Leider, J. E., Silverstein, S. C. (1975) Studies on the mechanism of phagocytosis. I. Requirements for circumferential attachment of particle-bound ligands to specific receptors on the macrophage plasma membrane J. Exp. Med 142,1263-1282[Abstract/Free Full Text]
218 - Staudinger, B. J., Oberdoerster, M. A., Lewis, P. J., Rosen, H. (2002) mRNA expression profiles for Escherichia coli ingested by normal and phagocyte oxidase-deficient human neutrophils J. Clin. Invest 110,1151-1163[CrossRef][Medline]
219 - Root, R. K., Stossel, T. P. (1974) Myeloperoxidase-mediated iodination by granulocytes. Intracellular site of operation and some regulating factors J. Clin. Invest 53,1207-1215
220 - Segal, A. W., Garcia, R. C., Harper, A. M. (1983) Iodination by stimulated human neutrophils. Studies on its stoichiometry, subcellular localization and relevance to microbial killing Biochem. J 210,215-225[Medline]
221 - Reeves, E. P., Nagl, M., Godovac-Zimmermann, J., Segal, A. W. (2003) Reassessment of the microbicidal activity of reactive oxygen species and hypochlorous acid with reference to the phagocytic vacuole of the neutrophil granulocyte J. Med. Microbiol 52,643-651[Abstract/Free Full Text]
222 - Klebanoff, S. J., Hamon, C. B. (1972) Role of myeloperoxidase-mediated antimicrobial systems in intact leukocytes J. Reticuloendothel. Soc 12,170-196[Medline]
223 - Odeberg, H., Olofsson, T., Olsson, I. (1974) Myeloperoxidase-mediated extracellular iodination during phagocytosis in granulocytes Scand. J. Haematol 12,155-160[Medline]
224 - Wu, W., Chen, Y., d’Avignon, A., Hazen, S. L. (1999) 3-Bromotyrosine and 3,5-dibromotyrosine are major products of protein oxidation by eosinophil peroxidase: potential markers for eosinophil-dependent tissue injury in vivo Biochemistry 38,3538-3548[CrossRef][Medline]
225 - Buss, I. H., Senthilmohan, R., Darlow, B. A., Mogridge, N., Kettle, A. J., Winterbourn, C. C. (2003) 3-Chlorotyrosine as a marker of protein damage by myeloperoxidase in tracheal aspirates from preterm infants: association with adverse respiratory outcome Pediatr. Res 53,455-462[CrossRef][Medline]
226 - Hazen, S. L., Heinecke, J. W. (1997) 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima J. Clin. Invest 99,2075-2081[Medline]
227 - van der Vliet, A., Nguyen, M. N., Shigenaga, M. K., Eiserich, J. P., Marelich, G. P., Cross, C. E. (2000) Myeloperoxidase and protein oxidation in cystic fibrosis Am. J. Physiol. Lung Cell. Mol. Physiol 279,L537-L546[Abstract/Free Full Text]
228 - Lamb, N. J., Gutteridge, J. M., Baker, C., Evans, T. W., Quinlan, G. J. (1999) Oxidative damage to proteins of bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome: evidence for neutrophil-mediated hydroxylation, nitration, and chlorination Crit. Care Med 27,1738-1744[CrossRef][Medline]
229 - Chapman, A. L., Hampton, M. B., Senthilmohan, R., Winterbourn, C. C., Kettle, A. J. (2002) Chlorination of bacterial and neutrophil proteins during phagocytosis and killing of Staphylococcus aureus J. Biol. Chem 277,9757-9762[Abstract/Free Full Text]
230 - Rosen, H., Crowley, J. R., Heinecke, J. W. (2002) Human neutrophils use the myeloperoxidase-hydrogen peroxide-chloride system to chlorinate but not nitrate bacterial proteins during phagocytosis J. Biol. Chem 277,30463-30468[Abstract/Free Full Text]
231 - Amin, V. M., Olson, N. F. (1968) Selective increase in hydrogen peroxide resistance of a coagulase-positive staphylococcus J. Bacteriol 95,1604-1607[Abstract/Free Full Text]
232 - Amin, V. M., Olson, N. F. (1968) Influence of catalase activity on resistance of coagulase-positive staphylococci to hydrogen peroxide Appl. Microbiol 16,267-270[Medline]
233 - Mandell, G. L. (1975) Catalase, superoxide dismutase, and virulence of Staphylococcus aureus. In vitro and in vivo studies with emphasis on staphylococcal-leukocyte interaction J. Clin. Invest 55,561-566
234 - Root, R. K. (1974) Correction of the function of chronic granulomatous disease (CGD) granulocytes (PMN) with extracellular H2O2 Clin. Res 22,452A
235 - Johnston, R. B., Jr, Baehner, R. L. (1970) Improvement of leukocyte bactericidal activity in chronic granulomatous disease Blood 35,350-355[Abstract/Free Full Text]
236 - Ismail, G., Boxer, L. A., Baehner, R. L. (1979) Utilization of liposomes for correction of the metabolic and bactericidal deficiencies in chronic granulomatous disease Pediatr. Res 13,769-773[Medline]
237 - Gerber, C. E., Bruchelt, G., Falk, U. B., Kimpfler, A., Hauschild, O., Kuci, S., Bachi, T., Niethammer, D., Schubert, R. (2001) Reconstitution of bactericidal activity in chronic granulomatous disease cells by glucose-oxidase-containing liposomes Blood 98,3097-3105[Abstract/Free Full Text]
238 - Kaplan, E. L., Laxdal, T., Quie, P. G. (1968) Studies of polymorphonuclear leukocytes from patients with chronic granulomatous disease of childhood: bactericidal capacity for streptococci Pediatrics 41,591-599[Abstract/Free Full Text]
239 - Klebanoff, S. J., White, L. R. (1969) Iodination defect in the leukocytes of a patient with chronic granulomatous disease of childhood N. Engl. J. Med 280,460-466
240 - Mandell, G. L., Hook, E. W. (1969) Leukocyte bactericidal activity in chronic granulomatous disease: correlation of bacterial hydrogen peroxide production and susceptibility to intracellular killing J. Bacteriol 100,531-532[Abstract/Free Full Text]
241 - Holmes, B., Good, R. A. (1972) Laboratory models of chronic granulomatous disease J. Reticuloendothel. Soc 12,216-237[Medline]
242 - Pitt, J., Bernheimer, H. P. (1974) Role of peroxide in phagocytic killing of pneumococci Infect. Immun 9,48-52[Abstract/Free Full Text]
243 - Shohet, S. B., Pitt, J., Baehner, R. L., Poplack, D. G. (1974) Lipid peroxidation in the killing of phagocytized pneumococci Infect. Immun 10,1321-1328[Abstract/Free Full Text]
244 - Klebanoff, S. J. (1970) Myeloperoxidase: contribution to the microbicidal activity of intact leukocytes Science 169,1095-1097[Abstract/Free Full Text]
245 - Koch, C. (1974) Effect of sodium azide upon normal and pathological granulocyte function Acta Pathol. Microbiol. Scand. B 82,136-142
246 - Lehrer, R. I. (1971) Inhibition by sulfonamides of the candidacidal activity of human neutrophils J. Clin. Invest 50,2498-2505
247 - Korchak, H. M., Roos, D., Giedd, K. N., Wynkoop, E. M., Vienne, K., Rutherford, L. E., Buyon, J. P., Rich, A. M., Weissmann, G. (1983) Granulocytes without degranulation: neutrophil function in granule-depleted cytoplasts Proc. Natl. Acad. Sci. USA 80,4968-4972[Abstract/Free Full Text]
248 - Roos, D., Voetman, A. A., Meerhof, L. J. (1983) Functional activity of enucleated human polymorphonuclear leukocytes J. Cell Biol 97,368-377[Abstract/Free Full Text]
249 - Odell, E. W., Segal, A. W. (1988) The bactericidal effects of the respiratory burst and the myeloperoxidase system isolated in neutrophil cytoplasts Biochim. Biophys. Acta 971,266-274[Medline]
250 - Schock, L., Vercellotti, G., Stroncek, D., Jacob, H. S. (1984) Use of lysosome-free PMN cytoplasts ("neutroplasts") uncovers the critical role of myeloperoxidase for target cell lysis Clin. Res 32,753A
251 - Stroncek, D. F., Vercellotti, G. M., Huh, P. W., Jacob, H. S. (1986) Neutrophil oxidants inactivate -1-protease inhibitor and promote PMN-mediated detachment of cultured endothelium. Protection by free methionine Arteriosclerosis 6,332-340[Abstract/Free Full Text]
252 - Lehrer, R. I., Cline, M. J. (1969) Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection J. Clin. Invest 48,1478-1488
253 - Lehrer, R. I., Hanifin, J., Cline, M. J. (1969) Defective bactericidal activity in myeloperoxidase-deficient human neutrophils Nature 223,78-79[CrossRef][Medline]
254 - Parry, M. F., Root, R. K., Metcalf, J. A., Delaney, K. K., Kaplow, L. S., Richar, W. J. (1981) Myeloperoxidase deficiency. Prevalence and clinical significance Ann. Intern. Med 95,293-301
255 - Kutter, D. (1998) Prevalence of myeloperoxidase deficiency: population studies using Bayer-Technicon automated hematology J. Mol. Med 76,669-675[CrossRef][Medline]
256 - Suzuki, K., Nunoi, H., Miyazaki, M., Koi, F. (2000) Prevalence of inherited myeloperoxidase deficiency in Japan Petrides, P. E. Nauseef, W. M. eds. The Peroxidase Multigene Family of Enzymes. Biochemical Basis and Clinical Applications ,145-149 Springer Berlin.
257 - Cramer, R., Soranzo, M. R., Dri, P., Rottini, G. D., Bramezza, M., Cirielli, S., Patriarca, P. (1982) Incidence of myeloperoxidase deficiency in an area of northern Italy: histochemical, biochemical and functional studies Br. J. Haematol 51,81-87[Medline]
258 - Hoy, A., Leininger-Muller, B., Kutter, D., Siest, G., Visvikis, S. (2002) Growing significance of myeloperoxidase in non-infectious diseases Clin. Chem. Lab. Med 40,2-8[CrossRef][Medline]
259 - Kutter, D., Devaquet, P., Vanderstocken, G., Paulus, J. M., Marchal, V., Gothot, A. (2000) Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit? Acta Haematol 104,10-15[CrossRef][Medline]
260 - Aratani, Y., Koyama, H., Nyui, S., Suzuki, K., Kura, F., Maeda, N. (1999) Severe impairment in early host defense against Candida albicans in mice deficient in myeloperoxidase Infect. Immun 67,1828-1836[Abstract/Free Full Text]
261 - Aratani, Y., Kura, F., Watanabe, H., Akagawa, H., Takano, Y., Suzuki, K., Maeda, N., Koyama, H. (2000) Differential host susceptibility to pulmonary infections with bacteria and fungi in mice deficient in myeloperoxidase J. Infect. Dis 182,1276-1279[CrossRef][Medline]
262 - Aratani, Y., Kura, F., Watanabe, H., Akagawa, H., Takano, Y., Suzuki, K., Dinauer, M. C., Maeda, N., Koyama, H. (2002) Critical role of myeloperoxidase and nicotinamide adenine dinucleotide phosphate-oxidase in high-burden systemic infection of mice with Candida albicans J. Infect. Dis 185,1833-1837[CrossRef][Medline]
263 - Aratani, Y., Kura, F., Watanabe, H., Akagawa, H., Takano, Y., Suzuki, K., Dinauer, M. C., Maeda, N., Koyama, H. (2002) Relative contributions of myeloperoxidase and NADPH-oxidase to the early host defense against pulmonary infections with Candida albicans and Aspergillus fumigatus Med. Mycol 40,557-563[Medline]
264 - Rosen, H., Michel, B. R. (1997) Redundant contribution of myeloperoxidase-dependent systems to neutrophil-mediated killing of Escherichia coli Infect. Immun 65,4173-4178[Abstract/Free Full Text]
265 - Klebanoff, S. J., Clark, R. A. (1978) The Neutrophil: Function and Clinical Disorders Amsterdam, North Holland.
266 - Klebanoff, S. J., Pincus, S. H. (1971) Hydrogen peroxide utilization in myeloperoxidase-deficient leukocytes: a possible microbicidal control mechanism J. Clin. Invest 50,2226-2229
267 - Cech, P., Papathanassiou, A., Boreux, G., Roth, P., Miescher, P. A. (1979) Hereditary myeloperoxidase deficiency Blood 53,403-411[Abstract/Free Full Text]
268 - Kitahara, M., Simonian, Y., Eyre, H. J. (1979) Neutrophil myeloperoxidase: a simple reproducible technique to determine activity J. Lab. Clin. Med 93,232-237[Medline]
269 - DeChatelet, L. R., Long, G. D., Shirley, P. S., Bass, D. A., Thomas, M. J., Henderson, F. W., Cohen, M. S. (1982) Mechanism of the luminol-dependent chemiluminescence of human neutrophils J. Immunol 129,1589-1593[Medline]
270 - Nauseef, W. M., Root, R. K., Malech, H. L. (1983) Biochemical and immunologic analysis of hereditary myeloperoxidse deficiency J. Clin. Invest 71,1297-1307
271 - Nauseef, W. M., Metcalf, J. A., Root, R. K. (1983) Role of myeloperoxidase in the respiratory burst of human neutrophils Blood 61,483-492[Abstract/Free Full Text]
272 - Stendahl, O., Coble, B-I., Dahlgren, C., Hed, J., Molin, L. (1984) Myeloperoxidase modulates the phagocytic activity of polymorphonuclear neutrophil leukocytes. Studies with cells from a myeloperoxidase-deficient patient J. Clin. Invest 73,366-373
273 - Dri, P., Soranzo, M. R., Cramer, R., Menegazzi, R., Miotti, V., Patriarca, P. (1985) Role of myeloperoxidase in respiratory burst of human polymorphonuclear leukocytes. Studies with myeloperoxidase-deficient subjects Inflammation 9,21-31[CrossRef][Medline]
274 - Dri, P., Cramer, R., Soranzo, M. R., Miotti, R., Menegazzi, R., Patriarca, P. (1984) Influence of myeloperoxidase on neutrophil functions: studies with MPO-deficient neutrophils Agents Actions 15,43-44[CrossRef]
275 - Jandl, R. C., Andre-Schwartz, J., Borges-Dubois, L., Kipnes, R. S., McMurrich, B. J., Babior, B. M. (1978) Termination of the respiratory burst in human neutrophils J. Clin. Invest 61,1176-1185
276 - Lynch, R. E., Fridovich, I. (1978) Permeation of the erythrocyte stroma by superoxide radical J. Biol. Chem 253,4697-4699[Abstract/Free Full Text]
277 - MacMicking, J. D., Nathan, C., Hom, G., Chartrain, N., Fletcher, D. S., Trumbauer, M., Stevens, K., Xie, Q. W., Sokol, K., Hutchinson, N. (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase Cell 81,641-650[CrossRef][Medline]
278 - Vazquez-Torres, A., Jones-Carson, J., Mastroeni, P., Ischiropoulos, H., Fang, F. C. (2000) Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. I. Effects on microbial killing by activated peritoneal macrophages in vitro J. Exp. Med 192,227-236[Abstract/Free Full Text]
279 - Murray, H. W., Teitelbaum, R. F. (1992) L-arginine-dependent reactive nitrogen intermediates and the antimicrobial effect of activated human mononuclear phagocytes J. Infect. Dis 165,513-517[Medline]
280 - Schneemann, M., Schoedon, G., Hofer, S., Blau, N., Guerrero, L., Schaffner, A. (1993) Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes J. Infect. Dis 167,1358-1363[Medline]
281 - Denis, M. (1994) Human monocytes/macrophages: NO or no NO? J. Leukoc. Biol 55,682-684[Abstract]
282 - Carreras, M. C., Pargament, G. A., Catz, S. D., Poderoso, J. J., Boveris, A. (1994) Kinetics of nitric oxide and hydrogen peroxide production and formation of peroxynitrite during the respiratory burst of human neutrophils FEBS Lett 341,65-68[CrossRef][Medline]
283 - Carreras, M. C., Catz, S. D., Pargament, G. A., Del Bosco, C. G., Poderoso, J. J. (1994) Decreased production of nitric oxide by human neutrophils during septic multiple organ dysfunction syndrome. Comparison with endotoxin and cytokine effects on normal cells Inflammation 18,151-161[CrossRef][Medline]
284 - Evans, T. J., Buttery, L. D., Carpenter, A., Springall, D. R., Polak, J. M., Cohen, J. (1996) Cytokine-treated human neutrophils contain inducible nitric oxide synthase that produces nitration of ingested bacteria Proc. Natl. Acad. Sci. USA 93,9553-9558[Abstract/Free Full Text]
285 - Nathan, C., Shiloh, M. U. (2000) Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens Proc. Natl. Acad. Sci. USA 97,8841-8848[Abstract/Free Full Text]
286 - Weinberg, J. B. (1998) Nitric oxide production and nitric oxide synthase type 2 expression by human mononuclear phagocytes: a review Mol. Med 4,557-591[Medline]
287 - Kroncke, K. D., Fehsel, K., Kolb-Bachofen, V. (1998) Inducible nitric oxide synthase in human diseases Clin. Exp. Immunol 113,147-156[CrossRef][Medline]
288 - Bogdan, C. (2001) Nitric oxide and the immune response Nat. Immunol 2,907-916[CrossRef][Medline]
289 - Weinberg, J. B., Misukonis, M. A., Shami, P. J., Mason, S. N., Sauls, D. L., Dittman, W. A., Wood, E. R., Smith, G. K., McDonald, B., Bachus, K. E. (1995) Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages Blood 86,1184-1195[Abstract/Free Full Text]
290 - Albina, J. E. (1995) On the expression of nitric oxide synthase by human macrophages. Why no NO? J. Leukoc. Biol 58,643-649[Abstract]
291 - Saran, M., Michel, C., Bors, W. (1990) Reaction of NO with O2–. Implications for the action of endothelium-derived relaxing factor (EDRF) Free Radic. Res. Commun 10,221-226[Medline]
292 - Koppenol, W. H., Moreno, J. J., Pryor, W. A., Ischiropoulos, H., Beckman, J. S. (1992) Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide Chem. Res. Toxicol 5,834-842[CrossRef][Medline]
293 - Huie, R. E., Padmaja, S. (1993) The reaction of NO with superoxide Free Radic. Res. Commun 18,195-199[Medline]
294 - Radi, R., Beckman, J. S., Bush, K. M., Freeman, B. A. (1991) Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide J. Biol. Chem 266,4244-4250[Abstract/Free Full Text]
295 - Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A., Freeman, B. A. (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide Proc. Natl. Acad. Sci. USA 87,1620-1624[Abstract/Free Full Text]
296 - Lymar, S. V., Khairutdinov, R. F., Hurst, J. K. (2003) Hydroxyl radical formation by O–O bond homolysis in peroxynitrous acid Inorg. Chem 42,5259-5266[CrossRef][Medline]
297 - Zhu, L., Gunn, C., Beckman, J. S. (1992) Bactericidal activity of peroxynitrite Arch. Biochem. Biophys 298,452-457[CrossRef][Medline]
298 - Brunelli, L., Crow, J. P., Beckman, J. S. (1995) The comparative toxicity of nitric oxide and peroxynitrite to Escherichia coli Arch. Biochem. Biophys 316,327-334[CrossRef][Medline]
299 - Hurst, J. K., Lymar, S. V. (1997) Toxicity of peroxynitrite and related reactive nitrogen species toward Escherichia coli Chem. Res. Toxicol 10,802-810[CrossRef][Medline]
300 - Lymar, S. V., Hurst, J. K. (1996) Carbon dioxide: physiological catalyst for peroxynitrite-mediated cellular damage or cellular protectant? Chem. Res. Toxicol 9,845-850[CrossRef][Medline]
301 - Pfeiffer, S., Lass, A., Schmidt, K., Mayer, B. (2001) Protein tyrosine nitration in mouse peritoneal macrophages activated in vitro and in vivo: evidence against an essential role of peroxynitrite FASEB J 15,2355-2364[Abstract/Free Full Text]
302 - Pfeiffer, S., Lass, A., Schmidt, K., Mayer, B. (2001) Protein tyrosine nitration in cytokine-activated murine macrophages. Involvement of a peroxidase/nitrite pathway rather than peroxynitrite J. Biol. Chem 276,34051-34058[Abstract/Free Full Text]
303 - Brennan, M. L., Wu, W., Fu, X., Shen, Z., Song, W., Frost, H., Vadseth, C., Narine, L., Lenkiewicz, E., Borchers, M. T., Lusis, A. J., Lee, J. J., Lee, N. A., Abu-Soud, H. M., Ischiropoulos, H., Hazen, S. L. (2002) A tale of two controversies: defining both the role of peroxidases in nitrotyrosine formation in vivo using eosinophil peroxidase and myeloperoxidase-deficient mice and the nature of peroxidase-generated reactive nitrogen species J. Biol. Chem 277,17415-17427[Abstract/Free Full Text]
304 - Hurst, J. K. (2002) Whence nitrotyrosine? J. Clin. Invest 109,1287-1289[CrossRef][Medline]
305 - van der Vliet, A., Eiserich, J. P., Halliwell, B., Cross, C. E. (1997) Formation of reactive nitrogen species during peroxidase-catalyzed oxidation of nitrite J. Biol. Chem 272,7617-7625[Abstract/Free Full Text]
306 - Eiserich, J. P., Hristova, M., Cross, C. E., Jones, A. D., Freeman, B. A., Halliwell, B., van der Vliet, A. (1998) Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils Nature 391,393-397[CrossRef][Medline]
307 - van Dalen, C. J., Winterbourn, C. C., Senthilmohan, R., Kettle, A. J. (2000) Nitrite as a substrate and inhibitor of myeloperoxidase. Implications for nitration and hypochlorous acid production at sites of inflammation J. Biol. Chem 275,11638-11644[Abstract/Free Full Text]
308 - Hazen, S. L., Zhang, R., Shen, Z., Wu, W., Podrez, E. A., MacPherson, J. C., Schmitt, D., Mitra, S. N., Mukhopadhyay, C., Chen, Y., Cohen, P. A., Hoff, H. F., Abu-Soud, H. M. (1999) Formation of nitric oxide-derived oxidants by myeloperoxidase in monocytes: pathways for monocyte-mediated protein nitration and lipid peroxidation in vivo Circ. Res 85,950-958[Abstract/Free Full Text]
309 - Ischiropoulos, H. (1998) Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species Arch. Biochem. Biophys 356,1-11[CrossRef][Medline]
310 - Jiang, Q., Hurst, J. K. (1997) Relative chlorinating, nitrating, and oxidizing capabilities of neutrophils determined with phagocytosable probes J. Biol. Chem 272,32767-32772[Abstract/Free Full Text]
311 - Baldus, S., Eiserich, J. P., Mani, A., Castro, L., Figueroa, M., Chumley, P., Ma, W., Tousson, A., White, C. R., Bullard, D. C., Brennan, M. L., Lusis, A. J., Moore, K. P., Freeman, B. A. (2001) Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration J. Clin. Invest 108,1759-1770[CrossRef][Medline]
312 - Eiserich, J. P., Cross, C. E., Jones, A. D., Halliwell, B., van der Vliet, A. (1996) Formation of nitrating and chlorinating species by reaction of nitrite with hypochlorous acid. A novel mechanism for nitric oxide-mediated protein modification J. Biol. Chem 271,19199-19208[Abstract/Free Full Text]
313 - Kono, Y. (1995) The production of nitrating species by the reaction between nitrite and hypochlorous acid Biochem. Mol. Biol. Int 36,275-283[Medline]
314 - Marcinkiewicz, J., Chain, B., Nowak, B., Grabowska, A., Bryniarski, K., Baran, J. (2000) Antimicrobial and cytotoxic activity of hypochlorous acid: interactions with taurine and nitrite Inflamm. Res 49,280-289[CrossRef][Medline]
315 - Whiteman, M., Hooper, D. C., Scott, G. S., Koprowski, H., Halliwell, B. (2002) Inhibition of hypochlorous acid-induced cellular toxicity by nitrite Proc. Natl. Acad. Sci. USA 99,12061-12066[Abstract/Free Full Text]
316 - Whiteman, M., Rose, P., Halliwell, B. (2003) Inhibition of hypochlorous acid-induced oxidative reactions by nitrite: is nitrite an antioxidant? Biochem. Biophys. Res. Commun 303,1217-1224[CrossRef][Medline]
317 - Carr, A. C., Frei, B. (2001) The nitric oxide congener nitrite inhibits myeloperoxidase/H2O2/Cl–-mediated modification of low density lipoprotein J. Biol. Chem 276,1822-1828[Abstract/Free Full Text]
318 - Abu-Soud, H. M., Hazen, S. L. (2000) Nitric oxide modulates the catalytic activity of myeloperoxidase J. Biol. Chem 275,5425-5430[Abstract/Free Full Text]
319 - Abu-Soud, H. M., Hazen, S. L. (2000) Nitric oxide is a physiological substrate for mammalian peroxidases J. Biol. Chem 275,37524-37532[Abstract/Free Full Text]
320 - Metchnikoff, E. (1905) Immunity in Infective Diseases ,182 Cambridge University Press Cambridge.
321 - Rous, P. (1925) The relative reaction within living mammalian tissues. I. General features of vital staining with litmus J. Exp. Med 41,379-397[Abstract/Free Full Text]
322 - Rous, P. (1925) The relative reaction within living mammalian tissues. II. On the mobilization of acid material within cells, and the reaction as influenced by the cell state J. Exp. Med 41,399-411[Abstract/Free Full Text]
323 - Sprick, M. G. (1956) Phagocytosis of M. tuberculosis and M. smegmatis stained with indicator dyes Am. Rev. Tuberc 74,552-565[Medline]
324 - Pavlov, E. P., Solov’ev, V. N. (1967) pH changes of cytoplasm in phagocytosis of microbes stained with indicator dyes Biull. Eksp. Biol. Med 63,78-81
325 - Jensen, M. S., Bainton, D. F. (1973) Temporal changes in pH within the phagocytic vacuole of the polymorphonuclear neutrophilic leukocyte J. Cell Biol 56,379-388[Abstract/Free Full Text]
326 - Mandell, G. L. (1970) Intraphagosomal pH of human polymorphonuclear neutrophils Proc. Soc. Exp. Biol. Med 134,447-449[CrossRef][Medline]
327 - Kakinuma, K. (1970) Metabolic control and intracellular pH during phagocytosis by polymorphonuclear leucocytes J. Biochem., (Tokyo) 68,177-185[Abstract/Free Full Text]
328 - Segal, A. W., Geisow, M., Garcia, R., Harper, A., Miller, R. (1981) The respiratory burst of phagocytic cells is associated with a rise in vacuolar pH Nature 290,406-409[CrossRef][Medline]
329 - Geisow, M. J., D’Arcy, H. P., Young, M. R. (1981) Temporal changes of lysosome and phagosome pH during phagolysosome formation in macrophages: studies by fluorescence spectroscopy J. Cell Biol 89,645-652[Abstract/Free Full Text]
330 - Cech, P., Lehrer, R. I. (1984) Phagolysosomal pH of human neutrophils Blood 63,88-95[Abstract/Free Full Text]
331 - Hurst, J. K., Albrich, J. M., Green, T. R., Rosen, H., Klebanoff, S. J. (1984) Myeloperoxidase-dependent fluorescein chlorination by stimulated neutrophils J. Biol. Chem 259,4812-4821[Abstract/Free Full Text]
332 - Jankowski, A., Scott, C. C., Grinstein, S. (2002) Determinants of the phagosomal pH in neutrophils J. Biol. Chem 277,6059-6066[Abstract/Free Full Text]
333 - Henderson, L. M. (2001) NADPH oxidase subunit gp91phox: a proton pathway Protoplasma 217,37-42[CrossRef][Medline]
334 - Henderson, L. M., Meech, R. W. (1999) Evidence that the product of the human X-linked CGD gene, gp91-phox, is a voltage-gated H(+) pathway J. Gen. Physiol 114,771-786[Abstract/Free Full Text]
335 - DeCoursey, T. E., Cherny, V. V., Morgan, D., Katz, B. Z., Dinauer, M. C. (2001) The gp91phox component of NADPH oxidase is not the voltage-gated proton channel in phagocytes, but it helps J. Biol. Chem 276,36063-36066[Abstract/Free Full Text]
336 - DeCoursey, T. E., Morgan, D., Cherny, V. V. (2002) The gp91phox component of NADPH oxidase is not a voltage-gated proton channel J. Gen. Physiol 120,773-779[Free Full Text]
337 - DeCoursey, T. E. (2003) Voltage-gated proton channels and other proton transfer pathways Physiol. Rev 83,475-579[Abstract/Free Full Text]
338 - van Zwieten, R., Wever, R., Hamers, M. N., Weening, R. S., Roos, D. (1981) Extracellular proton release by stimulated neutrophils J. Clin. Invest 68,310-313
339 - Elsbach, P., Weiss, J., Levy, O. (1999) Oxygen-independent antimicrobial systems of phagocytes Gallin, J. I. Snyderman, R. eds. Inflammation: Basic Principles and Clinical Correlates ,801-817 Lippincott Williams & Wilkins Philadelphia, PA.
340 - Ganz, T. (2003) Defensins: antimicrobial peptides of innate immunity Nat. Rev. Immunol 3,710-720[CrossRef][Medline]
341 - Ganz, T. (2004) Antimicrobial polypeptides J. Leukoc. Biol 75,34-38[Abstract/Free Full Text]
342 - Levy, O. (2004) Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes J. Leukoc. Biol 76,909-925[Abstract/Free Full Text]
343 - Olsson, I., Venge, P. (1972) Cationic proteins of human granulocytes. I. Isolation of the cationic proteins from the granules of leukaemic myeloid cells Scand. J. Haematol 9,204-214[Medline]
344 - Reeves, E. P., Lu, H., Jacobs, H. L., Messina, C. G., Bolsover, S., Gabella, G., Potma, E. O., Warley, A., Roes, J., Segal, A. W. (2002) Killing activity of neutrophils is mediated through activation of proteases by K+ flux Nature 416,291-297[CrossRef][Medline]
345 - Gratzer, W. (2002) Immunology: the Wright stuff Nature 416,275-277[Medline]
346 - Roos, D., Winterbourn, C. C. (2002) Immunology. Lethal weapons Science 296,669-671[Abstract/Free Full Text]
347 - Fang, F. C. (2004) Antimicrobial reactive oxygen and nitrogen species: concepts and controversies Nat. Rev. Microbiol 2,820-832[CrossRef][Medline]
348 - Tkalcevic, J., Novelli, M., Phylactides, M., Iredale, J. P., Segal, A. W., Roes, J. (2000) Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G Immunity 12,201-210[CrossRef][Medline]
349 - Belaaouaj, A., McCarthy, R., Baumann, M., Gao, Z., Ley, T. J., Abraham, S. N., Shapiro, S. D. (1998) Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis Nat. Med 4,615-618[CrossRef][Medline]
350 - Belaaouaj, A. (2002) Neutrophil elastase-mediated killing of bacteria: lessons from targeted mutagenesis Microbes Infect 4,1259-1264[CrossRef][Medline]
351 - MacIvor, D. M., Shapiro, S. D., Pham, C. T., Belaaouaj, A., Abraham, S. N., Ley, T. J. (1999) Normal neutrophil function in cathepsin G-deficient mice Blood 94,4282-4293[Abstract/Free Full Text]
352 - Belaaouaj, A., Kim, K. S., Shapiro, S. D. (2000) Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase Science 289,1185-1188[Abstract/Free Full Text]
353 - Lopez-Boado, Y. S., Espinola, M., Bahr, S., Belaaouaj, A. (2004) Neutrophil serine proteinases cleave bacterial flagellin, abrogating its host response-inducing activity J. Immunol 172,509-515[Abstract/Free Full Text]
354 - Ahluwalia, J., Tinker, A., Clapp, L. H., Duchen, M. R., Abramov, A. Y., Pope, S., Nobles, M., Segal, A. W. (2004) The large-conductance Ca2+-activated K+ channel is essential for innate immunity Nature 427,853-858[CrossRef][Medline]
355 - Harrison, R. E., Touret, N., Grinstein, S. (2002) Microbial killing: oxidants, proteases and ions Curr. Biol 12,R357-R359[CrossRef][Medline]
356 - DeCoursey, T. E. (2004) During the respiratory burst, do phagocytes need proton channels or potassium channels, or both? Sci. STKE May 11,pe21
357 - Rada, B. K., Geiszt, M., Kaldi, K., Timar, C., Ligeti, E. (2004) Dual role of phagocytic NADPH oxidase in bacterial killing Blood 104,2947-2953[Abstract/Free Full Text]
358 - Clark, R. A. (1983) Extracellular effects of the myeloperoxidase-hydrogen peroxide-halide system Weissmann, G. eds. Advances in Inflammation Research 5,107-146 Raven New York, NY.
359 - Fu, X., Kassim, S. Y., Parks, W. C., Heinecke, J. W. (2003) Hypochlorous acid generated by myeloperoxidase modifies adjacent tryptophan and glycine residues in the catalytic domain of matrix metalloproteinase-7 (matrilysin): an oxidative mechanism for restraining proteolytic activity during inflammation J. Biol. Chem 278,28403-28409[Abstract/Free Full Text]
360 - Klebanoff, S. J., Coombs, R. W. (1996) Virucidal effect of stimulated eosinophils on human immunodeficiency virus type 1 AIDS Res. Hum. Retroviruses 12,25-29[Medline]
361 - Klebanoff, S. J., Kazazi, F. (1995) Inactivation of human immunodeficiency virus type 1 by the amine oxidase-peroxidase system J. Clin. Microbiol 33,2054-2057[Abstract/Free Full Text]
362 - Klebanoff, S. J., Coombs, R. W. (1992) Viricidal effect of polymorphonuclear leukocytes on HIV-1: role of the myeloperoxidase system J. Clin. Invest 89,2014-2017
363 - Chase, M. J., Klebanoff, S. J. (1992) Viricidal effect of stimulated human mononuclear phagocytes on human immunodeficiency virus type 1 Proc. Natl. Acad. Sci. USA 89,5582-5585[Abstract/Free Full Text]
364 - Nathan, C. F., Murray, H. W., Wiebe, M. E., Rubin, B. Y. (1983) Identification of interferon- as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity J. Exp. Med 158,670-689[Abstract/Free Full Text]
365 - Legrand-Poels, S., Varia, D., Pincemail, J., Van de Vorst, A., Piette, J. (1990) Activation of human immunodeficiency virus type 1 by oxidative stress AIDS Res. Hum. Retroviruses 6,1389-1397[Medline]
366 - Schreck, R., Rieber, P., Baeuerle, P. A. (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-B transcription factor and HIV-1 EMBO J 10,2247-2258[Medline]
367 - Kazazi, F., Koehler, J. K., Klebanoff, S. J. (1996) Activation of the HIV long terminal repeat and viral production by H2O2-vanadate Free Radic. Biol. Med 20,813-820[CrossRef][Medline]
368 - Klebanoff, S. J., Mehlin, C., Headley, C. M. (1997) Activation of the HIV-1 long terminal repeat and viral replication by dimethylsulfoxide and related solvents AIDS Res. Hum. Retrovirises 13,1221-1227
369 - Klebanoff, S. J., Watts, D. H., Mehlin, C., Headley, C. M. (1999) Lactobacilli and vaginal host defense: activation of the human immunodeficiency virus type 1 long terminal repeat, cytokine production, and NF-B J. Infect. Dis 179,653-660[CrossRef][Medline]
370 - Klebanoff, S. J., Headley, C. M. (1999) Activation of the human immunodeficiency virus-1 long terminal repeat by respiratory burst oxidants of neutrophils Blood 93,350-356[Abstract/Free Full Text]
371 - Agner, K. (1947) Detoxicating effect of verdoperoxidase on toxins Nature 159,271-272
372 - Agner, K. (1950) Studies on peroxidative detoxification of purified diphtheria toxin J. Exp. Med 92,337-347[Abstract/Free Full Text]
373 - Clark, R. A., Klebanoff, S. J. (1979) Myeloperoxidase-mediated platelet release reaction J. Clin. Invest 63,177-183
374 - Clark, R. A., Klebanoff, S. J. (1980) Neutrophil-platelet interaction mediated by myeloperoxidase and hydrogen peroxide J. Immunol 124,399-405[Medline]
375 - Henderson, W. R., Chi, E. Y., Klebanoff, S. J. (1980) Eosinophil peroxidase-induced mast cell secretion J. Exp. Med 152,265-279[Abstract/Free Full Text]
376 - Chi, E. Y., Henderson, W. R. (1984) Ultrastructure of mast cell degranulation induced by eosinophil peroxidase: use of diaminobenzidine cytochemistry by scanning electron microscopy J. Histochem. Cytochem 32,337-341[Abstract]
377 - Stendahl, O., Molin, L., Lindroth, M. (1983) Granulocyte-mediated release of histamine from mast cells. Effect of myeloperoxidase and its inhibition by antiinflammatory sulfone compounds Int. Arch. Allergy Appl. Immunol 70,277-284[Medline]
378 - Lanza, F., Musto, P., Franze, D. (1985) Hereditary myeloperoxidase deficiency syndrome: clinical and haematological data of 10 cases Recenti Prog. Med 76,71-78[Medline]
379 - Lanza, F., Fietta, A., Spisani, S., Castoldi, G. L., Traniello, S. (1987) Does a relationship exist between neutrophil myeloperoxidase deficiency and the occurrence of neoplasms? J. Clin. Lab. Immunol 22,175-180[Medline]
380 - Lanza, F. (1998) Clinical manifestation of myeloperoxidase deficiency J. Mol. Med 76,676-681[CrossRef][Medline]
381 - Lanza, F., Giuliani, A. L., Amelotti, F., Spisani, S., Traniello, S., Castoldi, G. (1988) Depressed neutrophil-mediated tumor cell cytotoxicity in subjects affected by hereditary myeloperoxidase deficiency and secondary neoplasia Haematologica 73,355-358[Medline]
382 - London, S. J., Lehman, T. A., Taylor, J. A. (1997) Myeloperoxidase genetic polymorphism and lung cancer risk Cancer Res 57,5001-5003[Abstract/Free Full Text]
383 - van Zyl, J. M., Basson, K., van der Walt, B. J. (1989) Stimulation of the chlorinating activity of human myeloperoxidase by thyroid hormones and analogues Horm. Metab. Res 21,441-444[Medline]
384 - van Zyl, J. M., van der Walt, B. J., Kriegler, A. (1993) Thyroxine-supported oxidation in the myeloperoxidase system Horm. Metab. Res 25,569-572[Medline]
385 - Yip, C., Klebanoff, S. J. (1963) Synthesis in vitro of thyroxine from diiodotyrosine by myeloperoxidase and by a cell-free preparation of beef thyroid glands. I. Glucose-glucose oxidase system Biochim. Biophys. Acta 74,747-755[Medline]
386 - Taurog, A., Dorris, M. L. (1992) Myeloperoxidase-catalyzed iodination and coupling Arch. Biochem. Biophys 296,239-246[CrossRef][Medline]
387 - Klebanoff, S. J., Segal, S. J. (1960) The inactivation of estradiol by peroxidase J. Biol. Chem 235,52-55[Free Full Text]
388 - Klebanoff, S. J. (1977) Estrogen binding by leukocytes during phagocytosis J. Exp. Med 145,983-998[Abstract/Free Full Text]
389 - Tiruppathi, C., Naqvi, T., Wu, Y., Vogel, S. M., Minshall, R. D., Malik, A. B. (2004) Albumin mediates the transcytosis of myeloperoxidase by means of caveolae in endothelial cells Proc. Natl. Acad. Sci. USA 101,7699-7704[Abstract/Free Full Text]
390 - Piedrafita, F. J., Molander, R. B., Vansant, G., Orlova, E. A., Pfahl, M., Reynolds, W. F. (1996) An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element J. Biol. Chem 271,14412-14420[Abstract/Free Full Text]
391 - Reynolds, W. F., Chang, E., Douer, D., Ball, E. D., Kanda, V. (1997) An allelic association implicates myeloperoxidase in the etiology of acute promyelocytic leukemia Blood 90,2730-2737[Abstract/Free Full Text]
392 - Cascorbi, I., Henning, S., Brockmoller, J., Gephart, J., Meisel, C., Muller, J. M., Loddenkemper, R., Roots, I. (2000) Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant –463A of the myeloperoxidase gene Cancer Res 60,644-649[Abstract/Free Full Text]
393 - Le Marchand, L., Seifried, A., Lum, A., Wilkens, L. R. (2000) Association of the myeloperoxidase –463G a polymorphism with lung cancer risk Cancer Epidemiol. Biomarkers Prev 9,181-184[Abstract/Free Full Text]
394 - Schabath, M. B., Spitz, M. R., Zhang, X., Delclos, G. L., Wu, X. (2000) Genetic variants of myeloperoxidase and lung cancer risk Carcinogenesis 21,1163-1166[Abstract/Free Full Text]
395 - Kantarci, O. H., Lesnick, T. G., Yang, P., Meyer, R. L., Hebrink, D. D., McMurray, C. T., Weinshenker, B. G. (2002) Myeloperoxidase –463 (GA) polymorphism associated with lower risk of lung cancer Mayo Clin. Proc 77,17-22[Abstract/Free Full Text]
396 - Feyler, A., Voho, A., Bouchardy, C., Kuokkanen, K., Dayer, P., Hirvonen, A., Benhamou, S. (2002) Point: myeloperoxidase –463G a polymorphism and lung cancer risk Cancer Epidemiol. Biomarkers Prev 11,1550-1554[Abstract/Free Full Text]
397 - Schabath, M. B., Spitz, M. R., Delclos, G. L., Gunn, G. B., Whitehead, L. W., Wu, X. (2002) Association between asbestos exposure, cigarette smoking, myeloperoxidase (MPO) genotypes, and lung cancer risk Am. J. Ind. Med 42,29-37[CrossRef][Medline]
398 - Schabath, M. B., Spitz, M. R., Hong, W. K., Delclos, G. L., Reynolds, W. F., Gunn, G. B., Whitehead, L. W., Wu, X. (2002) A myeloperoxidase polymorphism associated with reduced risk of lung cancer Lung Cancer 37,35-40[CrossRef][Medline]
399 - Wu, X., Schabath, M. B., Spitz, M. R. (2003) Myeloperoxidase promoter region polymorphism and lung cancer risk Methods Mol. Med 75,121-133[Medline]
400 - Dally, H., Gassner, K., Jager, B., Schmezer, P., Spiegelhalder, B., Edler, L., Drings, P., Dienemann, H., Schulz, V., Kayser, K., Bartsch, H., Risch, A. (2002) Myeloperoxidase (MPO) genotype and lung cancer histologic types: the MPO –463 A allele is associated with reduced risk for small cell lung cancer in smokers Int. J. Cancer 102,530-535[CrossRef][Medline]
401 - Dally, H., Bartsch, H., Risch, A. (2003) Correspondence re: Feyler et al., point: myeloperoxidase (–463)G a polymorphism and lung cancer risk. Cancer Epidemiol. Biomark. Prev., 11: 1550–1554, 2002, and Xu et al., counterpoint: the myeloperoxidase (–463)G a polymorphism does not decrease lung cancer susceptibility in caucasians. 11: 1555–1559, 2002 Cancer Epidemiol. Biomarkers Prev 12,683[Free Full Text]
402 - Caporaso, N. E. (2002) Why have we failed to find the low penetrance genetic constituents of common cancers? Cancer Epidemiol. Biomarkers Prev 11,1544-1549[Free Full Text]
403 - Chevrier, I., Stucker, I., Houllier, A. M., Cenee, S., Beaune, P., Laurent-Puig, P., Loriot, M. A. (2003) Myeloperoxidase: new polymorphisms and relation with lung cancer risk Pharmacogenetics 13,729-739[CrossRef][Medline]
404 - Xu, L. L., Liu, G., Miller, D. P., Zhou, W., Lynch, T. J., Wain, J. C., Su, L., Christiani, D. C. (2002) Counterpoint: the myeloperoxidase –463G a polymorphism does not decrease lung cancer susceptibility in Caucasians Cancer Epidemiol. Biomarkers Prev 11,1555-1559[Abstract/Free Full Text]
405 - Misra, R. R., Tangrea, J. A., Virtamo, J., Ratnasinghe, D., Andersen, M. R., Barrett, M., Taylor, P. R., Albanes, D. (2001) Variation in the promoter region of the myeloperoxidase gene is not directly related to lung cancer risk among male smokers in Finland Cancer Lett 164,161-167[CrossRef][Medline]
406 - Hung, R. J., Boffetta, P., Brennan, P., Malaveille, C., Gelatti, U., Placidi, D., Carta, A., Hautefeuille, A., Porru, S. (2004) Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk Carcinogenesis 25,973-978[Abstract/Free Full Text]
407 - Pakakasama, S., Chen, T. T., Frawley, W., Muller, C., Douglass, E. C., Tomlinson, G. E. (2003) Myeloperoxidase promotor polymorphism and risk of hepatoblastoma Int. J. Cancer 106,205-207[CrossRef][Medline]
408 - Tsuruta, Y., Subrahmanyam, V. V., Marshall, W., O’Brien, P. J. (1985) Peroxidase-mediated irreversible binding of arylamine carcinogens to DNA in intact polymorphonuclear leukocytes activated by a tumor promoter Chem. Biol. Interact 53,25-35[CrossRef][Medline]
409 - Mallet, W. G., Mosebrook, D. R., Trush, M. A. (1991) Activation of (+–)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to diolepoxides by human polymorphonuclear leukocytes or myeloperoxidase Carcinogenesis 12,521-524[Abstract/Free Full Text]
410 - Petruska, J. M., Mosebrook, D. R., Jakab, G. J., Trush, M. A. (1992) Myeloperoxidase-enhanced formation of (+–)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene-DNA adducts in lung tissue in vitro: a role of pulmonary inflammation in the bioactivation of a procarcinogen Carcinogenesis 13,1075-1081[Abstract/Free Full Text]
411 - Josephy, P. D. (1996) The role of peroxidase-catalyzed activation of aromatic amines in breast cancer Mutagenesis 11,3-7[Abstract/Free Full Text]
412 - Henderson, J. P., Byun, J., Takeshita, J., Heinecke, J. W. (2003) Phagocytes produce 5-chlorouracil and 5-bromouracil, two mutagenic products of myeloperoxidase, in human inflammatory tissue J. Biol. Chem 278,23522-23528[Abstract/Free Full Text]
413 - Jiang, Q., Blount, B. C., Ames, B. N. (2003) 5-Chlorouracil, a marker of DNA damage from hypochlorous acid during inflammation. A gas chromatography-mass spectrometry assay J. Biol. Chem 278,32834-32840[Abstract/Free Full Text]
414 - Rojas, M., Godschalk, R., Alexandrov, K., Cascorbi, I., Kriek, E., Ostertag, J., Van Schooten, F. J., Bartsch, H. (2001) Myeloperoxidase –463A variant reduces benzo[a]pyrene diol epoxide DNA adducts in skin of coal tar-treated patients Carcinogenesis 22,1015-1018[Abstract/Free Full Text]
415 - Malle, E., Buch, T., Grone, H. J. (2003) Myeloperoxidase in kidney disease Kidney Int 64,1956-1967[CrossRef][Medline]
416 - Johnson, R. J., Lovett, D., Lehrer, R. I., Couser, W. G., Klebanoff, S. J. (1994) Role of oxidants and proteases in glomerular injury Kidney Int 45,352-359[Medline]
417 - Johnson, R. J., Couser, W. G., Chi, E. Y., Adler, S., Klebanoff, S. J. (1987) New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system J. Clin. Invest 79,1379-1387
418 - Johnson, R. J., Guggenheim, S. J., Klebanoff, S. J., Ochi, R. F., Wass, A., Baker, P., Schulze, M., Couser, W. G. (1988) Morphologic correlates of glomerular oxidant injury induced by the myeloperoxidase-hydrogen peroxide-halide system of the neutrophil Lab. Invest 58,294-301[Medline]
419 - Johnson, R. J., Klebanoff, S. J., Ochi, R. F., Adler, S., Baker, P., Sparks, L., Couser, W. G. (1987) Participation of the myeloperoxidase-H2O2-halide system in immune complex nephritis Kidney Int 32,342-349[Medline]
420 - Saeki, T., Kuroda, T., Morita, T., Suzuki, K., Arakawa, M., Kawasaki, K. (1995) Significance of myeloperoxidase in rapidly progressive glomerulonephritis Am. J. Kidney Dis 26,13-21[Medline]
421 - Xiao, H., Heeringa, P., Hu, P., Liu, Z., Zhao, M., Aratani, Y., Maeda, N., Falk, R. J., Jennette, J. C. (2002) Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice J. Clin. Invest 110,955-963[CrossRef][Medline]
422 - D’Agati, V. (2002) Antineutrophil cytoplasmic antibody and vasculitis: much more than a disease marker J. Clin. Invest 110,919-921[CrossRef][Medline]
423 - Reumaux, D., de Boer, M., Meijer, A. B., Duthilleul, P., Roos, D. (2003) Expression of myeloperoxidase (MPO) by neutrophils is necessary for their activation by anti-neutrophil cytoplasm autoantibodies (ANCA) against MPO J. Leukoc. Biol 73,841-849[Abstract/Free Full Text]
424 - Reynolds, W. F., Stegeman, C. A., Tervaert, J. W. (2002) –463 G/A myeloperoxidase promoter polymorphism is associated with clinical manifestations and the course of disease in MPO-ANCA-associated vasculitis Clin. Immunol 103,154-160[CrossRef][Medline]
425 - Pecoits-Filho, R., Stenvinkel, P., Marchlewska, A., Heimburger, O., Barany, P., Hoff, C. M., Holmes, C. J., Suliman, M., Lindholm, B., Schalling, M., Nordfors, L. (2003) A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients Kidney Int. Suppl May,S172-S176
426 - Ishida-Okawara, A., Oharaseki, T., Takahashi, K., Hashimoto, Y., Aratani, Y., Koyama, H., Maeda, N., Naoe, S., Suzuki, K. (2001) Contribution of myeloperoxidase to coronary artery vasculitis associated with MPO-ANCA production Inflammation 25,381-387[CrossRef][Medline]
427 - Suzuki, K. (2001) Neutrophil functions of patients with vasculitis related to myeloperoxidase-specific anti-neutrophil antibody Int. J. Hematol 74,134-143[Medline]
428 - Malle, E., Woenckhaus, C., Waeg, G., Esterbauer, H., Grone, E. F., Grone, H. J. (1997) Immunological evidence for hypochlorite-modified proteins in human kidney Am. J. Pathol 150,603-615[Abstract]
429 - Himmelfarb, J., McMenamin, M. E., Loseto, G., Heinecke, J. W. (2001) Myeloperoxidase-catalyzed 3-chlorotyrosine formation in dialysis patients Free Radic. Biol. Med 31,1163-1169[CrossRef][Medline]
430 - Johnson, K. J., Fantone, J. C. I., Kaplan, J., Ward, P. A. (1981) In vivo damage of rat lungs by oxygen metabolites J. Clin. Invest 67,983-993
431 - Cantin, A. M., North, S. L., Fells, G. A., Hubbard, R. C., Crystal, R. G. (1987) Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis J. Clin. Invest 79,1665-1673
432 - Buss, I. H., Darlow, B. A., Winterbourn, C. C. (2000) Elevated protein carbonyls and lipid peroxidation products correlating with myeloperoxidase in tracheal aspirates from premature infants Pediatr. Res 47,640-645[Medline]
433 - Hazen, S. L., Hsu, F. F., Gaut, J. P., Crowley, J. R., Heinecke, J. W. (1999) Modification of proteins and lipids by myeloperoxidase Methods Enzymol 300,88-105[Medline]
434 - Heinecke, J. W. (1999) Mechanisms of oxidative damage by myeloperoxidase in atherosclerosis and other inflammatory disorders J. Lab. Clin. Med 133,321-325[CrossRef][Medline]
435 - Chisolm, G. M., III, Hazen, S. L., Fox, P. L., Cathcart, M. K. (1999) The oxidation of lipoproteins by monocytes-macrophages. Biochemical and biological mechanisms J. Biol. Chem 274,25959-25962[Free Full Text]
436 - Heinecke, J. W. (1997) Mechanisms of oxidative damage of low density lipoprotein in human atherosclerosis Curr. Opin. Lipidol 8,268-274[Medline]
437 - Heinecke, J. W. (1998) Oxidants and antioxidants in the pathogenesis of atherosclerosis: implications for the oxidized low density lipoprotein hypothesis Atherosclerosis 141,1-15[Medline]
438 - Podrez, E. A., Abu-Soud, H. M., Hazen, S. L. (2000) Myeloperoxidase-generated oxidants and atherosclerosis Free Radic. Biol. Med 28,1717-1725[CrossRef][Medline]
439 - Heinecke, J. W. (1999) Mass spectrometric quantification of amino acid oxidation products in proteins: insights into pathways that promote LDL oxidation in the human artery wall FASEB J 13,1113-1120[Abstract/Free Full Text]
440 - Chisolm, G. M., Steinberg, D. (2000) The oxidative modification hypothesis of atherogenesis: an overview Free Radic. Biol. Med 28,1815-1826[CrossRef][Medline]
441 - Gaut, J. P., Heinecke, J. W. (2001) Mechanisms for oxidizing low-density lipoprotein. Insights from patterns of oxidation products in the artery wall and from mouse models of atherosclerosis Trends Cardiovasc. Med 11,103-112[CrossRef][Medline]
442 - Heinecke, J. W. (2003) Oxidative stress: new approaches to diagnosis and prognosis in atherosclerosis Am. J. Cardiol 91,12A-16A[Medline]
443 - Carr, A. C., Myzak, M. C., Stocker, R., McCall, M. R., Frei, B. (2000) Myeloperoxidase binds to low-density lipoprotein: potential implications for atherosclerosis FEBS Lett 487,176-180[CrossRef][Medline]
444 - Heinecke, J. W., Li, W., Mueller, D. M., Bohrer, A., Turk, J. (1994) Cholesterol chlorohydrin synthesis by the myeloperoxidase-hydrogen peroxide-chloride system: potential markers for lipoproteins oxidatively damaged by phagocytes Biochemistry 33,10127-10136[CrossRef][Medline]
445 - Panasenko, O. M., Evgina, S. A., Aidyraliev, R. K., Sergienko, V. I., Vladimirov, Y. A. (1994) Peroxidation of human blood lipoproteins induced by exogenous hypochlorite or hypochlorite generated in the system of "myeloperoxidase + H2O2 + Cl–" Free Radic. Biol. Med 16,143-148[CrossRef][Medline]
446 - Jerlich, A., Hammel, M., Horakova, L., Schaur, R. J. (2001) An improved method for the sensitive monitoring of low density lipoprotein modification by myeloperoxidase Redox Rep 6,257-264[CrossRef][Medline]
447 - Yang, C. Y., Gu, Z. W., Yang, M., Lin, S. N., Garcia-Prats, A. J., Rogers, L. K., Welty, S. E., Smith, C. V. (1999) Selective modification of apoB-100 in the oxidation of low density lipoproteins by myeloperoxidase in vitro J. Lipid Res 40,686-698[Abstract/Free Full Text]
448 - Yang, C-Y., Wang, J., Krutchinsky, A. N., Chait, B. T., Morrisett, J. D., Smith, C. V. (2001) Selective oxidation in vitro by myeloperoxidase of the N-terminal amine in apolipoprotein B-100 J. Lipid Res. 42,1891-1896[Abstract/Free Full Text]
449 - Carr, A. C., Decker, E. A., Park, Y., Frei, B. (2001) Comparison of low-density lipoprotein modification by myeloperoxidase-derived hypochlorous and hypobromous acids Free Radic. Biol. Med 31,62-72[CrossRef][Medline]
450 - Exner, M., Hermann, M., Hofbauer, R., Hartmann, B., Kapiotis, S., Gmeiner, B. (2004) Thiocyanate catalyzes myeloperoxidase-initiated lipid oxidation in LDL Free Radic. Biol. Med 37,146-155[Medline]
451 - Podrez, E. A., Schmitt, D., Hoff, H. F., Hazen, S. L. (1999) Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro J. Clin. Invest 103,1547-1560[Medline]
452 - Byun, J., Mueller, D. M., Fabjan, J. S., Heinecke, J. W. (1999) Nitrogen dioxide radical generated by the myeloperoxidase-hydrogen peroxide-nitrite system promotes lipid peroxidation of low density lipoprotein FEBS Lett 455,243-246[CrossRef][Medline]
453 - Heller, J. I., Crowley, J. R., Hazen, S. L., Salvay, D. M., Wagner, P., Pennathur, S., Heinecke, J. W. (2000) p-Hydroxyphenylacetaldehyde, an aldehyde generated by myeloperoxidase, modifies phospholipid amino groups of low density lipoprotein in human atherosclerotic intima J. Biol. Chem 275,9957-9962[Abstract/Free Full Text]
454 - Bergt, C., Marsche, G., Panzenboeck, U., Heinecke, J. W., Malle, E., Sattler, W. (2001) Human neutrophils employ the myeloperoxidase/hydrogen peroxide/chloride system to oxidatively damage apolipoprotein A-I Eur. J. Biochem 268,3523-3531[Medline]
455 - Bergt, C., Pennathur, S., Fu, X., Byun, J., O’Brien, K., McDonald, T. O., Singh, P., Anantharamaiah, G. M., Chait, A., Brunzell, J., Geary, R. L., Oram, J. F., Heinecke, J. W. (2004) The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport Proc. Natl. Acad. Sci. USA 101,13032-13037[Abstract/Free Full Text]
456 - McCormick, M. L., Gaut, J. P., Lin, T. S., Britigan, B. E., Buettner, G. R., Heinecke, J. W. (1998) Electron paramagnetic resonance detection of free tyrosyl radical generated by myeloperoxidase, lactoperoxidase, and horseradish peroxidase J. Biol. Chem 273,32030-32037[Abstract/Free Full Text]
457 - Leeuwenburgh, C., Rasmussen, J. E., Hsu, F. F., Mueller, D. M., Pennathur, S., Heinecke, J. W. (1997) Mass spectrometric quantification of markers for protein oxidation by tyrosyl radical, copper, and hydroxyl radical in low density lipoprotein isolated from human atherosclerotic plaques J. Biol. Chem 272,3520-3526[Abstract/Free Full Text]
458 - Whitman, S. C., Hazen, S. L., Miller, D. B., Hegele, R. A., Heinecke, J. W., Huff, M. W. (1999) Modification of type III VLDL, their remnants, and VLDL from ApoE- knockout mice by p-hydroxyphenylacetaldehyde, a product of myeloperoxidase activity, causes marked cholesteryl ester accumulation in macrophages Arterioscler. Thromb. Vasc. Biol 19,1238-1249[Abstract/Free Full Text]
459 - Daugherty, A., Dunn, J. L., Rateri, D. L., Heinecke, J. W. (1994) Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions J. Clin. Invest 94,437-444
460 - Malle, E., Waeg, G., Schreiber, R., Grone, E. F., Sattler, W., Grone, H. J. (2000) Immunohistochemical evidence for the myeloperoxidase/H2O2/halide system in human atherosclerotic lesions: colocalization of myeloperoxidase and hypochlorite-modified proteins Eur. J. Biochem 267,4495-4503[Medline]
461 - Sugiyama, S., Okada, Y., Sukhova, G. K., Virmani, R., Heinecke, J. W., Libby, P. (2001) Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes Am. J. Pathol 158,879-891[Abstract/Free Full Text]
462 - Malle, E., Hazell, L., Stocker, R., Sattler, W., Esterbauer, H., Waeg, G. (1995) Immunologic detection and measurement of hypochlorite-modified LDL with specific monoclonal antibodies Arterioscler. Thromb. Vasc. Biol 15,982-989[Abstract/Free Full Text]
463 - Hazell, L. J., Arnold, L., Flowers, D., Waeg, G., Malle, E., Stocker, R. (1996) Presence of hypochlorite-modified proteins in human atherosclerotic lesions J. Clin. Invest 97,1535-1544[Medline]
464 - Hazell, L. J., Baernthaler, G., Stocker, R. (2001) Correlation between intima-to-media ratio, apolipoprotein B-100, myeloperoxidase, and hypochlorite-oxidized proteins in human atherosclerosis Free Radic. Biol. Med 31,1254-1262[CrossRef][Medline]
465 - Woods, A. A., Linton, S. M., Davies, M. J. (2003) Detection of HOCl-mediated protein oxidation products in the extracellular matrix of human atherosclerotic plaques Biochem. J 370,729-735[CrossRef][Medline]
466 - Woods, A. A., Davies, M. J. (2003) Fragmentation of extracellular matrix by hypochlorous acid Biochem. J 376,219-227[CrossRef][Medline]
467 - Leeuwenburgh, C., Hardy, M. M., Hazen, S. L., Wagner, P., Oh-ishi, S., Steinbrecher, U. P., Heinecke, J. W. (1997) Reactive nitrogen intermediates promote low density lipoprotein oxidation in human atherosclerotic intima J. Biol. Chem 272,1433-1436[Abstract/Free Full Text]
468 - Beckman, J. S., Ye, Y. Z., Anderson, P. G., Chen, J., Accavitti, M. A., Tarpey, M. M., White, C. R. (1994) Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry Biol. Chem. Hoppe Seyler 375,81-88[Medline]
469 - Byun, J., Henderson, J. P., Mueller, D. M., Heinecke, J. W. (1999) 8-Nitro-2'-deoxyguanosine, a specific marker of oxidation by reactive nitrogen species, is generated by the myeloperoxidase-hydrogen peroxide-nitrite system of activated human phagocytes Biochemistry 38,2590-2600[CrossRef][Medline]
470 - Shishehbor, M. H., Aviles, R. J., Brennan, M. L., Fu, X., Goormastic, M., Pearce, G. L., Gokce, N., Keaney, J. F., Jr, Penn, M. S., Sprecher, D. L., Vita, J. A., Hazen, S. L. (2003) Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy JAMA 289,1675-1680[Abstract/Free Full Text]
471 - Kirk, E. A., Dinauer, M. C., Rosen, H., Chait, A., Heinecke, J. W., LeBoeuf, R. C. (2000) Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice Arterioscler. Thromb. Vasc. Biol 20,1529-1535[Abstract/Free Full Text]
472 - Noguchi, N., Nakano, K., Aratani, Y., Koyama, H., Kodama, T., Niki, E. (2000) Role of myeloperoxidase in the neutrophil-induced oxidation of low density lipoprotein as studied by myeloperoxidase-knockout mouse J. Biochem., (Tokyo) 127,971-976[Abstract/Free Full Text]
473 - Brennan, M. L., Anderson, M. M., Shih, D. M., Qu, X. D., Wang, X., Mehta, A. C., Lim, L. L., Shi, W., Hazen, S. L., Jacob, J. S., Crowley, J. R., Heinecke, J. W., Lusis, A. J. (2001) Increased atherosclerosis in myeloperoxidase-deficient mice J. Clin. Invest 107,419-430[Medline]
474 - Nauseef, W. M. (2001) The proper study of mankind J. Clin. Invest 107,401-403[Medline]
475 - Zhang, R., Brennan, M. L., Fu, X., Aviles, R. J., Pearce, G. L., Penn, M. S., Topol, E. J., Sprecher, D. L., Hazen, S. L. (2001) Association between myeloperoxidase levels and risk of coronary artery disease JAMA 286,2136-2142[Abstract/Free Full Text]
476 - Brennan, M. L., Penn, M. S., Van Lente, F., Nambi, V., Shishehbor, M. H., Aviles, R. J., Goormastic, M., Pepoy, M. L., McErlean, E. S., Topol, E. J., Nissen, S. E., Hazen, S. L. (2003) Prognostic value of myeloperoxidase in patients with chest pain N. Engl. J. Med 349,1595-1604[Abstract/Free Full Text]
477 - Baldus, S., Heeschen, C., Meinertz, T., Zeiher, A. M., Eiserich, J. P., Munzel, T., Simoons, M. L., Hamm, C. W. (2003) Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes Circulation 108,1440-1445[Abstract/Free Full Text]
478 - Cayley, W. E., Jr (2004) Prognostic value of myeloperoxidase in patients with chest pain N. Engl. J. Med 350,516-518[Free Full Text]
479 - Hiramatsu, K., Rosen, H., Heinecke, J. W., Wolfbauer, G., Chait, A. (1987) Superoxide initiates oxidation of low density lipoprotein by human monocytes Arteriosclerosis 7,55-60[Abstract]
480 - Llodra, J., Angeli, V., Liu, J., Trogan, E., Fisher, E. A., Randolph, G. J. (2004) Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques Proc. Natl. Acad. Sci. USA 101,11779-11784[Abstract/Free Full Text]
481 - Grayston, J. T. (2000) Background and current knowledge of Chlamydia pneumoniae and atherosclerosis J. Infect. Dis 181(Suppl. 3),S402-S410
482 - Ludewig, B., Krebs, P., Scandella, E. (2004) Immunopathogenesis of atherosclerosis J. Leukoc. Biol 76,300-306[Abstract/Free Full Text]
483 - Nagra, R. M., Becher, B., Tourtellotte, W. W., Antel, J. P., Gold, D., Paladino, T., Smith, R. A., Nelson, J. R., Reynolds, W. F. (1997) Immunohistochemical and genetic evidence of myeloperoxidase involvement in multiple sclerosis J. Neuroimmunol 78,97-107[CrossRef][Medline]
484 - Ramsaransing, G., Teelken, A., Prokopenko, V. M., Arutjunyan, A. V., De Keyser, J. (2003) Low leucocyte myeloperoxidase activity in patients with multiple sclerosis J. Neurol. Neurosurg. Psychiatry 74,953-955[Abstract/Free Full Text]
485 - Brennan, M., Gaur, A., Pahuja, A., Lusis, A. J., Reynolds, W. F. (2001) Mice lacking myeloperoxidase are more susceptible to experimental autoimmune encephalomyelitis J. Neuroimmunol 112,97-105[CrossRef][Medline]
486 - Reynolds, W. F., Rhees, J., Maciejewski, D., Paladino, T., Sieburg, H., Maki, R. A., Masliah, E. (1999) Myeloperoxidase polymorphism is associated with gender-specific risk for Alzheimer’s disease Exp. Neurol 155,31-41[CrossRef][Medline]
487 - Jolivalt, C., Leininger-Muller, B., Drozdz, R., Naskalski, J. W., Siest, G. (1996) Apolipoprotein E is highly susceptible to oxidation by myeloperoxidase, an enzyme present in the brain Neurosci. Lett 210,61-64[CrossRef][Medline]
488 - Jolivalt, C., Leininger-Muller, B., Bertrand, P., Herber, R., Christen, Y., Siest, G. (2000) Differential oxidation of apolipoprotein E isoforms and interaction with phospholipids Free Radic. Biol. Med 28,129-140[CrossRef][Medline]
489 - Green, P. S., Mendez, A. J., Jacob, J. S., Crowley, J. R., Growdon, W., Hyman, B. T., Heinecke, J. W. (2004) Neuronal expression of myeloperoxidase is increased in Alzheimer’s disease J. Neurochem 90,724-733[CrossRef][Medline]
490 - Reynolds, W. F., Hiltunen, M., Pirskanen, M., Mannermaa, A., Helisalmi, S., Lehtovirta, M., Alafuzoff, I., Soininen, H. (2000) MPO and APOE4 polymorphisms interact to increase risk for AD in Finnish males Neurology 55,1284-1290[Abstract/Free Full Text]
491 - Crawford, F. C., Freeman, M. J., Schinka, J. A., Morris, M. D., Abdullah, L. I., Richards, D., Sevush, S., Duara, R., Mullan, M. J. (2001) Association between Alzheimer’s disease and a functional polymorphism in the myeloperoxidase gene Exp. Neurol 167,456-459[CrossRef][Medline]
492 - Leininger-Muller, B., Hoy, A., Herbeth, B., Pfister, M., Serot, J. M., Stavljenic-Rukavina, M., Massana, L., Passmore, P., Siest, G., Visvikis, S. (2003) Myeloperoxidase G –463A polymorphism and Alzheimer’s disease in the ApoEurope study Neurosci. Lett 349,95-98[CrossRef][Medline]
493 - Combarros, O., Infante, J., Llorca, J., Pena, N., Fernandez-Viadero, C., Berciano, J. (2002) The myeloperoxidase gene in Alzheimer’s disease: a case-control study and meta-analysis Neurosci. Lett 326,33-36[CrossRef][Medline]
494 - Styczynska, M., Religa, D., Pfeffer, A., Luczywek, E., Wasiak, B., Styczynski, G., Peplonska, B., Gabryelewicz, T., Golebiowski, M., Kobrys, M., Barcikowska, M. (2003) Simultaneous analysis of five genetic risk factors in Polish patients with Alzheimer’s disease Neurosci. Lett 344,99-102[CrossRef][Medline]
495 - Hoy, A., Leininger-Muller, B., Poirier, O., Siest, G., Gautier, M., Elbaz, A., Amarenco, P., Visvikis, S. (2003) Myeloperoxidase polymorphisms in brain infarction. Association with infarct size and functional outcome Atherosclerosis 167,223-230[CrossRef][Medline]
496 - Wu, D. C., Teismann, P., Tieu, K., Vila, M., Jackson-Lewis, V., Ischiropoulos, H., Przedborski, S. (2003) NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease Proc. Natl. Acad. Sci. USA 100,6145-6150[Abstract/Free Full Text]
497 - Pennathur, S., Jackson-Lewis, V., Przedborski, S., Heinecke, J. W. (1999) Mass spectrometric quantification of 3-nitrotyrosine, ortho-tyrosine, and o,o'-dityrosine in brain tissue of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated mice, a model of oxidative stress in Parkinson’s disease J. Biol. Chem 274,34621-34628[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
W. Gottardi and M. Nagl
N-chlorotaurine, a natural antiseptic with outstanding tolerability
J. Antimicrob. Chemother.,
March 1, 2010;
65(3):
399 - 409.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. E. DeCoursey
Voltage-Gated Proton Channels Find Their Dream Job Managing the Respiratory Burst in Phagocytes
Physiology,
February 1, 2010;
25(1):
27 - 40.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. M. Prokopowicz, F. Arce, R. Biedron, C. L.-L. Chiang, M. Ciszek, D. R. Katz, M. Nowakowska, S. Zapotoczny, J. Marcinkiewicz, and B. M. Chain
Hypochlorous Acid: A Natural Adjuvant That Facilitates Antigen Processing, Cross-Priming, and the Induction of Adaptive Immunity
J. Immunol.,
January 15, 2010;
184(2):
824 - 835.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Hofmann Bowman, J. Wilk, A. Heydemann, G. Kim, J. Rehman, J. A. Lodato, J. Raman, and E. M. McNally
S100A12 Mediates Aortic Wall Remodeling and Aortic Aneurysm
Circ. Res.,
January 8, 2010;
106(1):
145 - 154.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Silva
When two is better than one: macrophages and neutrophils work in concert in innate immunity as complementary and cooperative partners of a myeloid phagocyte system
J. Leukoc. Biol.,
January 1, 2010;
87(1):
93 - 106.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Markovic, L. A. McCaig, J. Stephen, S. Mizuguchi, R. A. W. Veldhuizen, J. F. Lewis, and G. Cepinskas
Mediators released from LPS-challenged lungs induce inflammatory responses in liver vascular endothelial cells and neutrophilic leukocytes
Am J Physiol Gastrointest Liver Physiol,
December 1, 2009;
297(6):
G1066 - G1076.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Xu, S. Szep, and Z. Lu
The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases
PNAS,
December 1, 2009;
106(48):
20515 - 20519.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J. Frazier, X. Wang, L. M. Wancket, X.-A. Li, X. Meng, L. D. Nelin, A. C. B. Cato, and Y. Liu
Increased Inflammation, Impaired Bacterial Clearance, and Metabolic Disruption after Gram-Negative Sepsis in Mkp-1-Deficient Mice
J. Immunol.,
December 1, 2009;
183(11):
7411 - 7419.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Rosen, S. J. Klebanoff, Y. Wang, N. Brot, J. W. Heinecke, and X. Fu
Methionine oxidation contributes to bacterial killing by the myeloperoxidase system of neutrophils
PNAS,
November 3, 2009;
106(44):
18686 - 18691.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. B. Ambrosone, W. E. Barlow, W. Reynolds, R. B. Livingston, I-T. Yeh, J.-Y. Choi, W. Davis, J. M. Rae, L. Tang, L. R. Hutchins, et al.
Myeloperoxidase Genotypes and Enhanced Efficacy of Chemotherapy for Early-Stage Breast Cancer in SWOG-8897
J. Clin. Oncol.,
October 20, 2009;
27(30):
4973 - 4979.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Park and B. Mehrad
Innate Immunity to Aspergillus Species
Clin. Microbiol. Rev.,
October 1, 2009;
22(4):
535 - 551.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P.-Y. Cheng, A. Sham, and J. W. Kronstad
Cryptococcus gattii Isolates from the British Columbia Cryptococcosis Outbreak Induce Less Protective Inflammation in a Murine Model of Infection than Cryptococcus neoformans
Infect. Immun.,
October 1, 2009;
77(10):
4284 - 4294.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Rensen, Y. Slaats, J. Nijhuis, A. Jans, V. Bieghs, A. Driessen, E. Malle, J. W. Greve, and W. A. Buurman
Increased Hepatic Myeloperoxidase Activity in Obese Subjects with Nonalcoholic Steatohepatitis
Am. J. Pathol.,
October 1, 2009;
175(4):
1473 - 1482.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Carpena, P. Vidossich, K. Schroettner, B. M. Calisto, S. Banerjee, J. Stampler, M. Soudi, P. G. Furtmuller, C. Rovira, I. Fita, et al.
Essential Role of Proximal Histidine-Asparagine Interaction in Mammalian Peroxidases
J. Biol. Chem.,
September 18, 2009;
284(38):
25929 - 25937.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. DeLeo III, M. J. Gounis, B. Hong, J. C. Ford, A. K. Wakhloo, and A. A. Bogdanov Jr
Carotid Artery Brain Aneurysm Model: In Vivo Molecular Enzyme-specific MR Imaging of Active Inflammation in a Pilot Study
Radiology,
September 1, 2009;
252(3):
696 - 703.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. El Kebir, L. Jozsef, W. Pan, L. Wang, N. A. Petasis, C. N. Serhan, and J. G. Filep
15-Epi-lipoxin A4 Inhibits Myeloperoxidase Signaling and Enhances Resolution of Acute Lung Injury
Am. J. Respir. Crit. Care Med.,
August 15, 2009;
180(4):
311 - 319.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Schwartz, K. G. Leidal, J. K. Femling, J. P. Weiss, and W. M. Nauseef
Neutrophil Bleaching of GFP-Expressing Staphylococci: Probing the Intraphagosomal Fate of Individual Bacteria
J. Immunol.,
August 15, 2009;
183(4):
2632 - 2641.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Osterloh, F. Geisinger, M. Piedavent, B. Fleischer, N. Brattig, and M. Breloer
Heat shock protein 60 (HSP60) stimulates neutrophil effector functions
J. Leukoc. Biol.,
August 1, 2009;
86(2):
423 - 434.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. H. Vandal, C. F. Nathan, and S. Ehrt
Acid Resistance in Mycobacterium tuberculosis
J. Bacteriol.,
August 1, 2009;
191(15):
4714 - 4721.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. K. Schindhelm, L. P. van der Zwan, T. Teerlink, and P. G. Scheffer
Myeloperoxidase: A Useful Biomarker for Cardiovascular Disease Risk Stratification?
Clin. Chem.,
August 1, 2009;
55(8):
1462 - 1470.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Peterfi, A. Donko, A. Orient, A. Sum, A. Prokai, B. Molnar, Z. Vereb, E. Rajnavolgyi, K. J. Kovacs, V. Muller, et al.
Peroxidasin Is Secreted and Incorporated into the Extracellular Matrix of Myofibroblasts and Fibrotic Kidney
Am. J. Pathol.,
August 1, 2009;
175(2):
725 - 735.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. V. Lao, J. L. Herring, C. H. Kim, A. Darwanto, U. Soto, and L. C. Sowers
Incorporation of 5-chlorocytosine into mammalian DNA results in heritable gene silencing and altered cytosine methylation patterns
Carcinogenesis,
May 1, 2009;
30(5):
886 - 893.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Boelen, J. Kwakkel, C. W. Wieland, D. L. St. Germain, E. Fliers, and A. Hernandez
Impaired Bacterial Clearance in Type 3 Deiodinase-Deficient Mice Infected with Streptococcus pneumoniae
Endocrinology,
April 1, 2009;
150(4):
1984 - 1990.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Decano, J. C. Viereck, A. C. McKee, J. A. Hamilton, N. Ruiz-Opazo, and V. L.M. Herrera
Early-Life Sodium Exposure Unmasks Susceptibility to Stroke in Hyperlipidemic, Hypertensive Heterozygous Tg25 Rats Transgenic for Human Cholesteryl Ester Transfer Protein
Circulation,
March 24, 2009;
119(11):
1501 - 1509.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. T. H. Roelofs, K. M. A. Rouschop, G. J. D. Teske, G. T. M. Wagenaar, N. Claessen, J. J. Weening, T. van der Poll, and S. Florquin
Endogenous tissue-type plasminogen activator is protective during ascending urinary tract infection
Nephrol. Dial. Transplant.,
March 1, 2009;
24(3):
801 - 808.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-R. Liu, L. Tao, E. Gao, Y. Qu, W. B. Lau, B. L. Lopez, T. A. Christopher, W. Koch, T.-L. Yue, and X.-L. Ma
Rosiglitazone inhibits hypercholesterolaemia-induced myeloperoxidase upregulation--a novel mechanism for the cardioprotective effects of PPAR agonists
Cardiovasc Res,
February 1, 2009;
81(2):
344 - 352.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Maki, V. A. Tyurin, R. C. Lyon, R. L. Hamilton, S. T. DeKosky, V. E. Kagan, and W. F. Reynolds
Aberrant Expression of Myeloperoxidase in Astrocytes Promotes Phospholipid Oxidation and Memory Deficits in a Mouse Model of Alzheimer Disease
J. Biol. Chem.,
January 30, 2009;
284(5):
3158 - 3169.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. K. Rudolph, V. Rudolph, and S. Baldus
Contribution of Myeloperoxidase to Smoking-dependent Vascular Inflammation
Proceedings of the ATS,
December 1, 2008;
5(8):
820 - 823.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. E. DeCoursey
Voltage-gated proton channels: what's next?
J. Physiol.,
November 15, 2008;
586(22):
5305 - 5324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Yamashita, T. Miyoshi, T. Arai, N. Endo, H. Itoh, K. Makino, K. Mizugishi, T. Uchiyama, and M. Sasada
Ozone production by amino acids contributes to killing of bacteria
PNAS,
November 4, 2008;
105(44):
16912 - 16917.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Ashby
Inorganic Chemistry of Defensive Peroxidases in the Human Oral Cavity
Journal of Dental Research,
October 1, 2008;
87(10):
900 - 914.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Liu, Z. Jia, S. Soodvilai, G. Guan, M.-H. Wang, Z. Dong, J. D. Symons, and T. Yang
Nitro-oleic acid protects the mouse kidney from ischemia and reperfusion injury
Am J Physiol Renal Physiol,
October 1, 2008;
295(4):
F942 - F949.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Martner, C. Dahlgren, J. C. Paton, and A. E. Wold
Pneumolysin Released during Streptococcus pneumoniae Autolysis Is a Potent Activator of Intracellular Oxygen Radical Production in Neutrophils
Infect. Immun.,
September 1, 2008;
76(9):
4079 - 4087.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. C. Dale, L. Boxer, and W. C. Liles
The phagocytes: neutrophils and monocytes
Blood,
August 15, 2008;
112(4):
935 - 945.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. El Kebir, L. Jozsef, W. Pan, and J. G. Filep
Myeloperoxidase Delays Neutrophil Apoptosis Through CD11b/CD18 Integrins and Prolongs Inflammation
Circ. Res.,
August 15, 2008;
103(4):
352 - 359.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. E. Gandley, J. Rohland, Y. Zhou, E. Shibata, G. F. Harger, A. Rajakumar, V. E. Kagan, N. Markovic, and C. A. Hubel
Increased Myeloperoxidase in the Placenta and Circulation of Women With Preeclampsia
Hypertension,
August 1, 2008;
52(2):
387 - 393.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Omori, T. Ohira, Y. Uchida, S. Ayilavarapu, E. L. Batista Jr., M. Yagi, T. Iwata, H. Liu, H. Hasturk, A. Kantarci, et al.
Priming of neutrophil oxidative burst in diabetes requires preassembly of the NADPH oxidase
J. Leukoc. Biol.,
July 1, 2008;
84(1):
292 - 301.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Brovkovych, X.-P. Gao, E. Ong, S. Brovkovych, M.-L. Brennan, X. Su, S. L. Hazen, A. B. Malik, and R. A. Skidgel
Augmented inducible nitric oxide synthase expression and increased NO production reduce sepsis-induced lung injury and mortality in myeloperoxidase-null mice
Am J Physiol Lung Cell Mol Physiol,
July 1, 2008;
295(1):
L96 - L103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Marsche, P. G. Furtmuller, C. Obinger, W. Sattler, and E. Malle
Hypochlorite-modified high-density lipoprotein acts as a sink for myeloperoxidase in vitro
Cardiovasc Res,
July 1, 2008;
79(1):
187 - 194.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Swee, C. L. Wilson, Y. Wang, J. K. McGuire, and W. C. Parks
Matrix metalloproteinase-7 (matrilysin) controls neutrophil egress by generating chemokine gradients
J. Leukoc. Biol.,
June 1, 2008;
83(6):
1404 - 1412.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. G. Painter, R. W. Bonvillain, V. G. Valentine, G. A. Lombard, S. G. LaPlace, W. M. Nauseef, and G. Wang
The role of chloride anion and CFTR in killing of Pseudomonas aeruginosa by normal and CF neutrophils
J. Leukoc. Biol.,
June 1, 2008;
83(6):
1345 - 1353.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Rudolph, T. K. Rudolph, and B. A. Freeman
Blood pressure regulation: role for neutrophils?
Blood,
May 15, 2008;
111(10):
4840 - 4840.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Bjorling, C. Lindskog, P. Oksvold, J. Linne, C. Kampf, S. Hober, M. Uhlen, and F. Ponten
A Web-based Tool for in Silico Biomarker Discovery Based on Tissue-specific Protein Profiles in Normal and Cancer Tissues
Mol. Cell. Proteomics,
May 1, 2008;
7(5):
825 - 844.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yona, H.-H. Lin, P. Dri, J. Q. Davies, R. P. G. Hayhoe, S. M. Lewis, S. E. M. Heinsbroek, K. A. Brown, M. Perretti, J. Hamann, et al.
Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function
FASEB J,
March 1, 2008;
22(3):
741 - 751.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Zhu, J. Pi, S. Wachi, M. E. Andersen, R. Wu, and Y. Chen
Identification of Nrf2-dependent airway epithelial adaptive response to proinflammatory oxidant-hypochlorous acid challenge by transcription profiling
Am J Physiol Lung Cell Mol Physiol,
March 1, 2008;
294(3):
L469 - L477.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Haegens, J. H. J. Vernooy, P. Heeringa, B. T. Mossman, and E. F. M. Wouters
Myeloperoxidase modulates lung epithelial responses to pro-inflammatory agents
Eur. Respir. J.,
February 1, 2008;
31(2):
252 - 260.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Matthijsen, D. Huugen, N. T. Hoebers, B. de Vries, C. J. Peutz-Kootstra, Y. Aratani, M. R. Daha, J. W. C. Tervaert, W. A. Buurman, and P. Heeringa
Myeloperoxidase Is Critically Involved in the Induction of Organ Damage after Renal Ischemia Reperfusion
Am. J. Pathol.,
December 1, 2007;
171(6):
1743 - 1752.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Kanayama and Y. Miyamoto
Apoptosis triggered by phagocytosis-related oxidative stress through FLIPS down-regulation and JNK activation
J. Leukoc. Biol.,
November 1, 2007;
82(5):
1344 - 1352.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Talalay, J. W. Fahey, Z. R. Healy, S. L. Wehage, A. L. Benedict, C. Min, and A. T. Dinkova-Kostova
Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation
PNAS,
October 30, 2007;
104(44):
17500 - 17505.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Marsche, B. Weigle, W. Sattler, and E. Malle
Soluble RAGE blocks scavenger receptor CD36-mediated uptake of hypochlorite-modified low-density lipoprotein
FASEB J,
October 1, 2007;
21(12):
3075 - 3082.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Goedken, S. McCormick, K. G. Leidal, K. Suzuki, Y. Kameoka, J. M. Astern, M. Huang, A. Cherkasov, and W. M. Nauseef
Impact of Two Novel Mutations on the Structure and Function of Human Myeloperoxidase
J. Biol. Chem.,
September 21, 2007;
282(38):
27994 - 28003.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Chandra, H. Haines, C. Michie, and A. Maheshwari
Developmental Defects in Neutrophils from Preterm Infants
NeoReviews,
September 1, 2007;
8(9):
e368 - e376.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. Reed, S. J. Heydrick, C. B. Aarons, S. Prushik, A. C. Gower, A. F. Stucchi, and J. M. Becker
A neurokinin-1 receptor antagonist that reduces intra-abdominal adhesion formation decreases oxidative stress in the peritoneum
Am J Physiol Gastrointest Liver Physiol,
September 1, 2007;
293(3):
G544 - G551.
[Abstract]
[Full Text]
[PDF]
|
TOP
ABSTRACT
INTRODUCTION