Originally published online as doi:10.1189/jlb.0505286 on October 21, 2005
Published online before print October 21, 2005
(Journal of Leukocyte Biology. 2006;79:7-15.)
© 2006
by Society for Leukocyte Biology
Activation of human eosinophils via P2 receptors: novel findings and future perspectives
Davide Ferrari*,1,
Andrea la Sala
,
Elisabeth Panther
,
Johannes Norgauer
,
Francesco Di Virgilio* and
Marco Idzko||
* Department of Experimental and Diagnostic Medicine, Section of General Pathology and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Italy;
Laboratory of Molecular and Cellular Biology, IRCCS, San Raffaele, Rome, Italy;
Department of Gastroenterology, University of Freiburg, Germany;
Department of Dermatology, University of Jena, Germany; and
|| Department of Pneumology, University of Freiburg, Germany
1 Correspondence: Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy. E-mail: dfr{at}unife.it
ABSTRACT
A growing body of information indicates that release of intracellular
nucleotides represents an important way to modulate several
cell pathways in physiological or pathological conditions. Nucleotides
released as a consequence of cell damage, cell stress, bacterial
infection, or other noxious stimuli signal at a class of plasma
membrane receptors—P2 receptors—activating diverse
intracellular pathways in many tissues and organs. For example,
nucleotides secreted in the airway system control chloride/liquid
secretion, goblet cell degranulation, and ciliary beat frequency.
Several studies indicate that nucleotides play a role in airway
diseases through their action on multiple cell types, including
mast cells, dendritic cells, neurons, and eosinophils. Recent
work by us and other groups led to the identification and characterization
of P2 receptors expressed by human eosinophils. In this review,
we will summarize recent developments in this field and put
forward a hypothesis about the role of P2 receptors in pathophysiological
conditions where eosinophils are major players.
Key Words: extracellular nucleotides • inflammation
INTRODUCTION
Eosinophils are major effector cells in different pathological
conditions such as atopic diseases, rhinitis, eczema, asthma,
and parasitic infections [
1
2
3
4
5
]. Activation and migration
of eosinophils to inflammatory sites are induced by microbial
products, allergens, activated complement components, chemokines,
and cytokines [
6
]. "Nonimmune" mediators, such as the poorly
characterized factors released from virally infected, stressed,
or necrotic cells, are also under investigation for their capacity
to activate and recruit immune cells [
7
]. Nucleotides are present
at high concentration within the cells and can be actively released
or diffuse out of mechanically stressed, infected, or injured
cells (
Fig. 1
) [
8
9
10
11
]. Once in the extracellular milieu,
they are degraded rapidly by nucleotide-metabolizing enzymes
(ecto-nucleotidases) expressed on the membrane of several cell
types [
12
13
14
]. The nucleotide extracellular concentration,
which is normally low in healthy tissues, may raise the following
tissue damage and be sensed by surrounding cells expressing
P2 receptors.
The different sensitivity to nucleotides of the diverse P2 subtypes
allows activation of different subsets of P2 receptors as the
concentration of the nucleotide increases. Little is known about
responses elicited by extracellular nucleotides in human eosinophils.
The interesting study by Burgers and colleagues [
9
] elegantly
demonstrated that thrombin-stimulated platelets secrete a chemotactic
factor attracting eosinophils, and this substance is adenosine
5'-triphosphate (ATP). These findings prompted us to investigate
the expression and function of these receptors in eosinophil
cells, to identify new, potential targets for the modulation
of eosinophil responses, and to develop novel therapies for
allergy and parasitic diseases.
EOSINOPHIL CELLS
Approximately 120 years ago, Paul Ehrlich [
15
] described granular
leukocytes that had high affinity for the acidic dye eosin and
named these cells eosinophils, which develop in the bone marrow
from CD34
+ progenitor cells. The differentiation process requires
8 days and is mainly regulated by the transcription factors
GATA-1, GATA-2, and CCAAT/enhancer-binding proteins [
16
17
18
],
which provide "instructive" signals cooperating with the "permissive"
eosinophil growth factors IL-3, IL-5, and granulocyte macrophage-colony
stimulating factor (GM-CSF). In particular, IL-5 has been recognized
as an eosinophil-active cytokine, responsible for differentiation,
proliferation, and release of eosinophil cells from the bone
marrow [
19
,
20
]. On the contrary, allergen challenge of patients
with allergic rhinitis and asthma causes a decline in the number
of their precursors, as well as of mature eosinophils in the
peripheral blood [
21
22
23
].
Once released from the bone marrow, eosinophils circulate in the peripheral blood for 8–12 h and finally home in specific tissues, predominantly gut and lung, where they reside for at least 1 week [24
].
The steps required for eosinophil trafficking from peripheral blood to tissues have been the subject of active investigation [20
, 25
26
27
], and numerous inflammatory mediators, including IL-1, IL-3, IL-4, IL-5, IL-9, IL-13, GM-CSF, RANTES, monocyte chemoattractant protein 3 (MCP-3), MCP-4, CC chemokine ligand 11 (CCL11; eotaxin-1), CCL24 (eotaxin-2), and CCL26 (eotaxin-3), have been implicated in the regulation of eosinophil accumulation [24
, 28
29
30
]. IL-3, IL-5, and GM-CSF enhance eosinophil production, maturation, and release into the blood as well as their effector functions; however, they show only weak chemotactic activity for the recruitment of eosinophils into tissues [24
, 31
32
33
]. Other T helper cell type 2 cytokines, namely IL-4 and IL-13, regulate eosinophil trafficking by increasing expression of the adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and P-selectin glycoprotein ligand 1 by epithelial cells and by up-regulating expression of eotaxin by bronchial epithelial cells and fibroblasts [24
, 26
, 31
]. IL-1, IL-12, and tumor necrosis factor 
(TNF-) also regulate eosinophil trafficking by promoting up-regulation of adhesion molecules, VCAM-1 included, on the endothelium [27
, 34
, 35
]. In contrast, IL-6 and IL-11 seem to decrease tissue eosinophilia by inhibiting VCAM-1 expression and production of type 2 cytokines [36
, 37
].
CCL11 (eotaxin-1), CCL24 (eotaxin-2), and CCL26 (eotaxin-3) are important factors for eosinophil recruitment. These three chemokines also increase adhesion of eosinophils to epithelial cells through up-regulation of very late antigen 4 (VLA-4) expression. VLA-4–VCAM-1 interaction then promotes eosinophil migration into tissues [24
, 38
].
Besides cytokines and chemokines, leukotriene B4 (LTB4), prostaglandin D2 (PGD2), complement factor 5a (C5a), and platelet-activating factor (PAF) are also potent eosinophil chemotactic factors [39
40
41
].
EOSINOPHIL ACTIVATION
Once in the tissues, eosinophils can be activated by a number
of different mediators. Hematopoietins, such as IL-3, IL-5,
and GM-CSF, "prime" eosinophils by increasing their responses
to various agonists, including lipid mediators, complement factors,
and chemokines, and as a result of their antiapoptotic effect,
promote eosinophil survival in the tissues [
42
43
44
]. Eosinophils
obtained from bronchoalveolar lavage (BAL), after allergen challenge,
show a primed phenotype, supporting the in vivo relevance of
priming. The second signal needed for the activation process
is provided by additional mediators such as PAF, PGD
2, lysophosphatidic
acid, CC chemokines, and complement factors C3a and C5a [
41
,
44
45
46
47
]. Primed or activated eosinophils often exhibit
lower density than resting ones, and for this reason, they are
also named hypodense eosinophils [
48
].
In line with their physiological function in defense of host mucosal surfaces, eosinophils can also be activated by cross-linking of immunoglobulin G (IgG) or IgA [48
]. In addition, it has been reported that eosinophils from donors with peripheral eosinophilia can be activated with anti-IgE or IgE-coated parasites. Binding of IgE to the high-affinity IgE receptor has been proposed as an activation stimulus; however, some reports cast doubts on functional expression of high-affinity IgE receptors in human eosinophils [49
50
51
].
EOSINOPHIL MEDIATORS AND EFFECTOR FUNCTIONS
Eosinophils release a variety of proinflammatory mediators,
including granule-stored cationic proteins, leukotrienes, and
cytokines {IL-1, IL-5, IL-8, and transforming growth factor-ß
(TGF-ß) [
24
,
52
53
54
]}. The granular cationic proteins,
major basic protein (MBP)-1, MBP-2, ECP, eosinophil-derived
neurotoxin (EDN), and eosinophil peroxidase (EPO), are endowed
of proinflammatory effects and play a role in host defense as
well as in the pathogenesis of diseases, where eosinophils are
implicated [
24
,
54
]. High levels of MBP, EPO, and ECP can
be found in serum and/or BAL from patients with eosinophilia,
due to bronchial asthma, atopic dermatitis, helminth infection,
or eosinophilic gastroenteritis. These mediators are cytotoxic
for different cell types in vitro and in vivo [
24
,
55
56
57
58
59
60
61
62
63
64
65
].
ECP and EDN, which belong to the RNase A superfamily, kill single-stranded RNA pneumoviruses [66
, 67
]. Furthermore, ECP can form voltage-insensitive, nonselective pores in the membrane of target cells, thus facilitating the entry of toxic molecules [68
]. MBP also triggers degranulation of mast cells and basophils [52
, 54
, 69
]. Eosinophil peroxidase generates microbiocidal hypohalous acids [52
, 54
, 69
]. Production and release of reactive oxygen species and lysosomal hydrolases cause further eosinophil-mediated toxicity, damaging parasite structures but also surrounding tissues [24
, 52
, 54
].
In addition, eosinophils are able to generate huge amounts of LTC4, which is metabolized into its active metabolites LTD4 and LTE4 [24
, 70
], inducing smooth muscle contraction, mucous secretion, and vascular permeability increase. These lipid mediators may amplify the inflammatory cascade by acting as chemotactic factors or by triggering the release of cytotoxic proteins [70
, 71
]. Another potentially toxic inflammatory mediator released by activated eosinophils is PAF, which also plays a role in the perpetuation of the local immune response [72
].
Last but not least, eosinophils produce a plethora of cytokines, including GM-CSF, IL-1, TGF-ß, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF- [24
, 52
, 54
, 73
]. However, most of these cytokines are produced by eosinophils in a low amount compared with the level secreted by other inflammatory cells such as T cells [74
, 75
]; therefore, it cannot be excluded that in some in vitro experiments, these cytokines were released by contaminating lymphocytes. It has been shown recently that eosinophils can act as antigen-presenting cells [24
, 76
, 77
]; however, they are relatively inefficient in T cell activation if compared with professional antigen-presenting cells {e.g., dendritic cells (DC), macrophages, B lymphocytes [77
]}. Although eosinophils are rare in the peripheral blood of healthy subjects, blood and tissue eosinophilia are typical hallmarks of allergic diseases (atopic dermatitis and bronchial asthma), gastrointestinal disorders (eosinophilic esophagitis, gastritis, gastroenteritis, and colitis), and helminth infection [78
, 79
]. In the last years, as a result of the large body of evidence supporting the critical role of eosinophils in the pathogenesis of asthma, there were extensive attempts to target eosinophils in the therapy of asthma. Corticosteroids down-regulate eosinophil counts in blood, sputum, BAL, and airway tissue, decreasing disease severity and improving symptoms. It has also been reported that some lung cancers show eosinophil infiltration. Tumor-associated tissue eosinophilia has a positive prognostic influence in squamous cell carcinomas and pulmonary adenocarcinoma [80
81
82
83
].
P2 RECEPTORS
Nucleotides have an acknowledged role as extracellular messengers,
as they are released by many cell types and specifically stimulate
a class of plasma membrane receptors—P2 receptors—thus
eliciting diverse responses depending on cell type and receptor
subtypes expressed [
84
85
86
87
88
]. P2 receptors are activated
by nucleotides, and on the basis of pharmacological, functional,
and cloning data, two P2 receptor subfamilies have been described
so far: P2Y and P2X [
84
,
89
,
90
].
P2Y receptors are seven membrane-spanning, G-protein-coupled receptors [91
]. Their activation triggers generation of inositol 1,4,5-trisphosphate and release of Ca2+ from the intracellular stores. P2Y receptors are ubiquitous, being expressed by monocytes, macrophages, DC, neurons, smooth and striated muscle cells, as well as epithelial and endothelial cells. Eight P2Y subtypes have been cloned so far (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) [91
92
93
].
P2Y1 mRNA expression is widespread, present in platelets, neurons, heart, skeletal muscle, and digestive tract [91
]; its stimulation is linked to platelet aggregation and nitric oxide release [94
]. The P2Y2 receptor is expressed in skeletal muscle, heart, lung, spleen, and kidney [91
]. Its function has been linked to ion transport in epithelia [95
]. The P2Y4 receptor is present in the intestine, lung, and placenta [91
]. Expression of P2Y6 has been found in many human tissues, including spleen, thymus, placenta, intestine, lung, and brain [91
, 96
, 97
]. The P2Y11 subtype has been found in corneal epithelia, endothelial, and pancreatic duct cells, promyelocytic HL-60 cells, DC, and lymphocytes, and its activation has been shown to be associated with increased intracellular concentration of cyclic adenosine monophosphate [98
99
100
101
].
The P2Y12 receptor is expressed in platelets, CD34+ stem cells, mast cells, and vascular smooth muscle cells [102
103
104
]. P2Y13 is expressed in bone marrow, spleen, liver, brain, airway epithelial cells, red blood cells, monocytes, DC, and T cells [105
, 106
]. The recently identified P2Y14 subtype has been found in hematopoietic cells, monocyte-derived DC, and human airway epithelial cells [93
, 107
].
Extensive pharmacological studies performed in P2Y-transfected cells revealed that the preferred ligand at P2Y11 is ATP and at P2Y1, P2Y12, and P2Y13 is adenosine 5'-diphosphate (ADP) [106
107
108
109
110
111
]. In contrast, the P2Y2, P2Y4, and P2Y6 subtypes are responsive to uridine nucleotides. P2Y2 is activated with similar efficiency by ATP and uridine 5'-triphosphate (UTP), which with uridine 5'-diphosphate (UDP), are potent agonists at P2Y4 and P2Y6, respectively [112
113
114
]. In addition, it has been shown that P2Y14 specifically responds to UDP-glucose and related sugar nucleotides but not to ATP, ADP, UTP, or UDP [93
, 106
, 115
116
117
118
].
P2X receptors are ligand-gated ion channels activated by extracellular ATP and selective for monovalent and divalent cations [119
120
121
]. The amino- and carboxyl-terminal domains are cytoplasmic. Seven different monomers have been cloned so far and named P2X1–P2X7. P2X subunits aggregate to form homo- or in some cases heteromultimers. These channels were identified originally in mammalian sensory neurons and subsequently, also found in several additional cell types such as smooth muscle, fibroblasts, lymphocytes, macrophages, and DC [90
]. Upon binding of the agonist, some P2X receptors (P2X1 and P2X3) desensitize rapidly, and others (P2X2, P2X4, and P2X7) show little or no desensitization [120
]. In contrast to P2Y receptors, all P2X subtypes are activated by ATP.
The P2X1 receptor is expressed by smooth muscle cells, megakariocytes, platelets, lymphocytes, DC, epithelial cells, ventricular myocardium, and neurons [122
123
124
125
126
].
P2X2 has different functional splice variants and is mainly expressed in pancreatic cells. 2-Methylthio-ATP is a better agonist than ATP for the P2X2 subtype; the ATP-derivative ß-methyleneATP (ß-meATP) and ß
-meATP are inactive at this receptor. A decrease in pH enhances the responsiveness of the P2X2 receptor to ATP. The P2X3 receptor is expressed by neurons, and its activation has been linked to nociceptive signaling [127
, 128
]. mRNA expression of this subtype has also been found in keratinocytes and CD43+ hematopoietic cell precursors [126
]. This receptor is potently activated by ß-meATP. The P2X4 subtype is distributed widely in human tissues. It has been found in neurons, hematopoietic cell precursors, macrophages, monocyte-derived DC, fibroblasts, and keratinocytes [129
130
131
]. P2X5 and P2X6 mRNAs have been detected in neurons, keratinocytes, and thyrocytes [132
, 133
]. The P2X7 receptor [134
], previously known as P2Z [135
], is a protein subunit of 595 amino acids, which assembles in the plasma membrane to form multimeric complexes of unknown stoichiometry. It is expressed in immune and nonimmune cells. Macrophages, microglial, and DC express the receptor at high levels [87
]. The P2X7 subunit has a long carboxyl-terminal domain, allowing the receptor to undergo a transition from a cationic, selective plasma membrane channel to a large plasma membrane pore. The permeability transition occurs upon stimulation of the receptor with high or pulsed ATP doses. The pore stays open as long as ATP is present. Elimination of ATP causes resealing of the plasma membrane. Synthetic ligands are based on the ATP structure, among which 2',3'-(4-benzoyl)benzoyl-ATP (BzATP) is more potent than ATP at activating the P2X7 receptor [136
].
P2 RECEPTOR-MEDIATED RESPONSES OF EOSINOPHILS
Saito and colleagues [
137
], who stimulated human cord blood-derived
eosinophils and human peripheral eosinophils with ATP, ADP,
and guanosine 5'-triphosphate (GTP), studied responses elicited
by pharmacological stimulation of eosinophils with extracellular
nucleotides. They showed that cord blood-derived eosinophils
migrated toward nucleotides and suggested that as ATP is released
by autonomic nerves and activated platelets, this nucleotide
could modulate eosinophil functions in vivo. It was later shown
by Burgers and colleagues [
9
] that thrombin-activated platelets
secreted ATP. The nucleotide was able to induce an increase
in the intracellular Ca
2+ concentration of eosinophil cells
and to stimulate them to chemotact toward platelets [
9
]. The
seminal observations by Saito and Burgers and colleagues were
later confirmed by the identification of eosinophil P2Y and
P2X receptors.
Human eosinophils express mRNA for the following P2Y and P2X subtypes: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y14, P2X1, P2X4, and P2X7 (refs. [138
139
140
] and Tobias Müller and M. Idzko, unpublished observations). Stimulation of P2 receptors expressed by eosinophils induces multiple cell responses including intracellular calcium transients, CD11b expression, actin polymerization, chemotaxis, production of reactive oxygen metabolites, secretion of IL-8, and ECP.
Stimuli as different as bacterial peptides, IgE cross-linking agents, the complement protein C5a, and recombinant human eotaxin, induce Ca2+ changes in eosinophils. Data from other cell types show that ATP and other nucleotides trigger Ca2+ increase by stimulating P2X and P2Y purinoceptor subtypes. In human eosinophils incubated in the presence of extracellular Ca2+, ATP triggered a rapid and dose-dependent Ca2+ spike followed by a slowly decreasing plateau. When eosinophils are stimulated with nucleotides in the absence of extracellular Na+, the ATP- and BzATP-induced Ca2+ rise elicited is about twice as high as in the presence of Na+, pointing to a competition between Na+ and Ca2+ for entering through the ATP-activated receptor channel, and the UTP- or ADP-triggered calcium increase is not affected. The ATP-triggered Ca2+ spike is also present in the absence of the extracellular cations, an indication that ATP also induces the Ca2+ release from the intracellular stores [140
, 141
]. Furthermore, pretreatment of human eosinophils with pertussis toxin (an inhibitor of Gi-proteins, which regulates the activation of phospholipase C) completely abolished an ADP- and UTP-induced Ca2+ response, and it reduces the ATP-triggered Ca2+ rise by 60%. These observations indicate that human eosinophils express functional P2Y receptors [141
, 142
]. Although incubation of eosinophils with ATP does not affect the C5a-triggered Ca2+ rise, stimulation with the nucleotide prior to UTP treatment completely abrogates the Ca2+ rise induced by UTP, suggesting that ATP, in contrast to UTP, acts at two different receptor subtypes [140
].
Actin reorganization/polymerization is normally preceded by a Ca2+ concentration increase and sometimes preludes to cell locomotion. In eosinophils, nucleotides cause a rapid and transient polymerization of actin molecules in a concentration-dependent manner. The kinetics of the process is fast and transient, and an increase in f-actin content reaches a maximum after 30 s from the stimulation and the return to control values, within 5 min [140
, 141
]. The use of selective P2Y and P2X receptor agonist as well as pretreatment of human eosinophils with EGTA and pertussis toxin revealed that P2Y receptors are involved in ATP-induced actin polymerization. Consistently, eosinophil chemotaxis is stronger in response to P2Y rather than P2X agonists [140
, 141
].
Following activation, changes of eosinophil cell-surface expression of adhesion molecules CD11b and L-selectin occur, influencing migration from peripheral blood to the site of inflammation. Prestored CD11b molecules are redistributed quickly from the cytoplasmic vesicle to the cell membrane. It has been shown by using calcium ionophores and intracellular calcium chelators that up-regulation of CD11b expression at the cell surface is regulated tightly by intracellular calcium rises in eosinophils and neutrophils [143
]. Once this receptor is at the cell surface, it binds to the endothelial intercellular adhesion molecule-1 (ICAM-1), favoring migration of eosinophils into tissues.
Walker and colleagues [144
] showed a considerably increased expression of CD11b in eosinophils from sputum, nasal polyps, and BAL of asthmatic subjects compared with blood eosinophils [144
]. Augmented expression of this molecule was induced by endothelial cells stimulated with IL-1ß, presumably through the release of PAF or interaction with the adhesion molecules endothelial leukocyte adhesion molecule-1, VCAM-1, and ICAM-1.
Nucleotides induce, in a concentration-dependent manner, a rapid CD11b up-regulation; half-maximal and maximal responses are at 30 s and 4 min, respectively. P2Y and P2X receptor agonists induce similar effects on CD11b up-regulation [141
]. The fact that extracellular ATP induces CD11b expression in human eosinophils and the ability of endothelial cells to release nucleotides open the possibility that ATP or other nucleotides may participate in this endothelial-mediated response.
Stimulation of human eosinophils with recombinant eotaxin, C3a, or C5a induces generation of ROIs. ATP triggers in these cells production of ROIs to a level comparable with that obtained by C5a. ADP, UTP, GTP, and BzATP are also able to induce production of ROIs, suggesting participation of different nucleotide receptors. However, as in the case of actin polymerization and migration, P2Y agonists are more active than P2X agonists in inducing ROIs production [140
].
ECP is a granule-associated mediator, single-chain, zinc-containing protein with a molecular weight ranging from 16 to 22 kDa, depending on the glycosylation level. As a result of activity and homology with RNases, ECP is also named "RNase 3" [145
]. Cytotoxic or cytostatic effects of ECP have been widely described [146
], and ECP is used as a marker of eosinophil activation in diseases, as its level correlates with eosinophil counts [147
]. In vitro degradation of myofibrillar and membrane-associated cytoskeletal proteins by ECP was also shown, suggesting a role for the protein in the pathogenesis of "eosinophilic myopathies" [148
].
A number of cytokines have been shown to attract eosinophils to the inflammatory focus in the tissue, including the chemokine IL-8. An increased secretion of IL-8 has been described in eosinophils from patients with bronchial asthma or atopic dermatitis [149
], and IL-8 concentration in BAL fluids from asthmatic patients is increased significantly in comparison with that of healthy subjects [149
].
Stimulation of eosinophils with nucleotides induces the release of ECP and IL-8. It is interesting that release of the two proteins has a different nucleotide requirement. Release of ECP is triggered in a dose-dependent manner by ATP, UTP, and UDP but not by BzATP, ADP, and ,ß-meATP. Although on the contrary, release of IL-8 is triggered by UDP, ATP, ,ß-meATP, and BzATP but not by UTP or ADP, suggesting the involvement of different P2 receptor subtypes. Moreover, pertussis toxin abrogates nucleotide-stimulated ECP but not IL-8 release. Therefore, secretion of ECP is likely a result of stimulation of a receptor of the P2Y subfamily (possibly P2Y2), and on the contrary, nucleotide-stimulated secretion of IL-8 can be a result of activation of P2Y (P2Y6) and P2X, possibly P2X1 and P2X7 receptors [150
].
CONCLUSIONS AND FUTURE PERSPECTIVES
It is increasingly clear that nucleotides/nucleotide receptors/nucleotide
metabolizing enzymes form a ubiquitous signal transduction and
regulatory system. This network plays a key role in the airway
system, where in physiological conditions, it modulates cell
functions such as chloride/liquid secretion, goblet cell degranulation,
and ciliary beat frequency [
151
152
153
]. Less known is the
involvement of the purinergic system in pathological conditions.
However, it is impressive to note that inhalation of aerosolized
ATP triggers a dramatic bronchoconstriction in healthy as well
as in asthmatic subjects and that ATP is much more potent than
two well-known bronchoconstrictive agents such as methacoline
and histamine, respectively [
154
].
Eosinophils have been implicated in the initiation of different inflammatory conditions in the lung through their actions on mast cells, DC, neurons, and eosinophils [155
, 156
].
A broad panel of chemotactic and chemokinetic factors is produced and released during inflammation and is responsible for tissue infiltration of immune cells, including eosinophils [157
]. ATP release may occur as a consequence of secretion, cell damage, or cell death; therefore, ATP-stimulated pathways might contribute to the pathogenesis of eosinophil-mediated tissue damage. The increased ATPase activity of leukocytes from asthmatic subjects could be an attempt of the organism to counteract an increased nucleotide secretion [158
, 159
]. A chemotactic role for ATP and UTP has been shown in vitro in different immune cells; it is thus not surprising that nucleotides can also exert this role in eosinophils, as demonstrated by experiments performed by using activated platelets. The ability of nucleotides to mediate responses such as chemotaxis, proliferation, cytokine production, or cell death opens an entirely new perspective for the development of anti-inflammatory drugs. The pharmacological modulation of nucleotide-mediated signal transduction in eosinophils and other immune cells represents an attractive new therapy for acute and chronic inflammatory diseases. P2 receptor blockers may be developed to the purpose of blocking eosinophil activation, and moreover, as a result of the effect of nucleotides on eosinophil survival, development of new P2 receptor blockers would be desirable for reducing the eosinophil lifespan in pathological conditions where this is detrimental. Extracellular ATP, UTP, or their derivatives may have potential use as therapeutic agents for airways diseases including cystic fibrosis, asthma, and chronic bronchitis [160
]. Another important consideration is that asthmatic individuals have a stronger peripheral response to agonists than normal individuals. This would be in accordance with the observation that eosinophils of asthmatic individuals express at a higher level some P2 purinergic subtypes and are more sensitive to ATP than those of healthy subjects (M. Idzko, unpublished observations). Eosinophil heterogeneity, in terms of cell density, membrane receptor expression, and function, may also be true for P2 receptors. It is a future challenge to identify differences in purinergic receptor expression and function in different eosinophil subpopulations. Many questions about the expression and function of P2 receptors in these cells remain unanswered. Identification of the entire panel of P2 receptors expressed by eosinophils could help to establish their role in modulating eosinophil responses in physiological and pathological conditions. Eosinophils are thought to cause tissue injury in a variety of pathological states by virtue of their highly histotoxic content of metabolites. For this reason, it would be interesting to characterize the panel of cytokine/chemokines as well as biologically active compounds released upon stimulation of eosinophils via P2 receptor triggering and responsible for eosinophil-mediated tissue remodeling.
Received May 31, 2005;
accepted August 22, 2005.
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October 3, 2008;
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