Journal of Leukocyte Biology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published online as doi:10.1189/jlb.0805488 on August 29, 2006

Published online before print August 29, 2006
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.0805488v1
80/6/1308    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tokita, K.
Right arrow Articles by Yamamoto, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tokita, K.
Right arrow Articles by Yamamoto, T.
(Journal of Leukocyte Biology. 2006;80:1308-1319.)
© 2006 by Society for Leukocyte Biology

Roles of leukocytosis and cysteinyl leukotriene in polymorphonuclear leukocyte-dependent plasma extravasation

Kazutaka Tokita*,1, Yasuhiro Uchida{dagger} and Tetsuro Yamamoto*

* Department of Molecular Pathology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; and
{dagger} Development Regulatory Affairs Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

1 Correspondence: Department of Molecular Pathology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811 Japan. E-mail: ktokita{at}kaiju.medic.kumamoto-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The PMN-dependent plasma extravasation is a major mechanism of permeability enhancement in acute inflammation. To reveal the pathophysiological significance of the PMN-dependent plasma extravasation, we prepared a systemic leukocytotic guinea pig model by a daily injection of recombinant human (rh)G-CSF. The extent of the PMN-dependent plasma extravasation, regarded as the late-phase permeability induced by an intradermal injection of zymosan-activated guinea pig plasma (ZAP) or of rhC5a, clearly correlated to the circulating PMN number. The augmentation of local response following the systemic response seemed to be the characteristic feature of the PMN-dependent plasma extravasation. We then revealed the molecular mechanism of the PMN-dependent plasma extravasation. Neither the antihistaminic agent diphenhydramine, nor the bradykinin B2 receptor antagonist, HOE140, affected the ZAP-induced, late-phase extravasation. In contrast to this, pretreatment with an antagonist of cysteinyl leukotriene (cys-LT) 1 receptor, pranlukast, significantly reduced the late-phase extravasation. Similarly, it was reduced by pretreatment with a 5-lipoxygenase inhibitor, MK-886, indicating the participation of cys-LTs in the PMN-dependent plasma extravasation. Histologically, pretreatment with pranlukast or MK-886 did not affect the ZAP-induced PMN infiltration. Consistently, a combined treatment with pranlukast and diphenhydramine completely suppressed the early-phase extravasation. As pranlukast pretreatment did not affect plasma extravasation induced by mast cell degranulation, and depletion of platelets did not influence the pranlukast-inhibitable plasma extravasation induced by rhC5a injection, cys-LTs are most likely produced by transcellular biosynthesis involving PMNs and vascular wall cells.

Key Words: complement C5a • mast cells • histamine • bradykinin • G-CSF


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The acute inflammatory reaction appears as a dynamic combination of arteriolar dilatation, plasma extravasation, and leukocyte infiltration, each of which interacts with one another. Among these component responses, two aspects of the interaction between plasma extravasation and leukocyte infiltration are clearly known. One is the presence of chemical mediators that induce both of the reactions. The other is the plasma extravasation associated to the PMN infiltration, also known as the PMN-dependent plasma extravasation.

The PMN-dependent plasma extravasation was initially described using intradermal (i.d.) leukocyte chemotactic factor injection models of rabbit [1 2 3 4 ]. This phenomenon was confirmed later in the human; the edema formation caused by an i.d. injection of C5a was less marked in bone marrow failure patients [5 ] and in neutropenic patients [6 ]. We have demonstrated that PMN-dependent plasma extravasation is specific to PMN infiltration by showing that monocyte infiltration does not accompany plasma extravasation, even in the monocytotic state of peripheral circulation [7 ].

However, despite its specific role, the pathophysiological significance of this phenomenon is not clear. Leukocytosis, or granulocytosis, in peripheral blood is a hallmark of systemic inflammatory response. It is believed that circulating leukocytosis plays a role in locally augmenting the leukocyte recruitment at the inflammatory lesion. This allowed us to hypothesize that the circulating leukocytosis would also augment the PMN-dependent plasma extravasation, resulting in an efficient recruitment of inflammatory plasma components at the site of inflammation. To examine this hypothesis, we prepared leukocytotic guinea pigs by daily administration of recombinant human (rh)G-CSF and quantitatively analyzed the correlation between the circulating PMN number and the intensity of plasma extravasation induced by C5a.

The plasma extravasation in inflammation is usually classified into two types: the PMN-dependent and the permeability factor-mediated plasma extravasation. In the latter, histamine (and other amines), bradykinin (and other kinin peptides), and leukotriene C4 [LTC4; and other cysteinyl LTs (cys-LTs)] are the major representatives. C5a also induces the permeability factor-mediated plasma extravasation by stimulating connective tissue mast cells to release histamine [8 ], in addition to the induction of PMN-dependent plasma extravasation. It is believed that these permeability factors bind to their own receptors on vascular endothelial cells at the postcapillary venule, resulting in the interendothelial gap formation and/or enhancement of the transendothelial vesicular transport [9 10 11 ].

In terms of the mechanism of the PMN-dependent plasma extravasation, it was possible that the extravasation was simply a leakage of plasma during the passage of leukocytes at the postcapillary venule wall. However, we recently discarded this possibility when we observed that monocyte infiltration does not accompany plasma extravasation and that the PMN-dependent plasma extravasation occurs before PMN extravasation [7 ]. This strongly suggests the possibility that the PMN-dependent plasma extravasation is caused by a specific interaction between PMNs and endothelial cells. However, its definite mechanism is still unclear.

Another possibility would contemplate the participation of one of the chemical mediators in the PMN-dependent plasma extravasation. First, defensins, antimicrobial peptides found in PMN granules, have been shown to induce histamine release from rat peritoneal mast cells within 10 s [12 ], suggesting the possibility that histamine released from connective tissue mast cells adjacent to the postcapillary venule would mediate the PMN-dependent plasma extravasation. Second, PMN exposition to high and low molecular weight kininogens [13 ] could lead to PMN-dependent plasma extravasation mediated by bradykinin or related kinins liberated from the kininogens on PMNs. Furthermore, in a mutant mouse deficient for a receptor of cys-LTs (cys-LT1 receptor), the extent of plasma extravasation in zymosan-induced peritonitis was significantly less than that in the wild-type animal, although the intensity of PMN infiltration did not differ between them [14 ]. This report suggests the participation of cys-LTs in the PMN-dependent plasma extravasation.

Based on these three possibilities, we have examined the inhibitory effect of an antihistaminic agent, a bradykinin B2 receptor antagonist, and a cys-LT1 receptor antagonist on the PMN-dependent plasma extravasation induced by an i.d. C5a injection in guinea pigs. In the present study, the cys-LT1 receptor antagonist and a 5-lipoxygenase (5-LO) inhibitor significantly suppressed the PMN-dependent plasma extravasation. We assume that cys-LTs would be produced in cooperation between PMNs and postcapillary venule endothelial cells and mediate the plasma extravasation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Materials
Chugai Pharmaceutical Corp. (Tokyo, Japan) provided the rhG-CSF; Shionogi Pharmaceutical Corp. (Osaka, Japan) provided cyclophosphamide; Ono Pharmaceutical Corp. (Osaka, Japan) provided a cys-LT1 receptor antagonist, pranlukast (ONO-1078); Merck Frosst Canada and Co. (Quebec) provided a 5-LO inhibitor, MK-886; a bradykinin B2 receptor antagonist, HOE140, was a product of Hoechst AG (Frankfurt, Germany); zymosan, rhC5a, histamine, diphenhydramine hydrochloride, compound 48/80, OVA, LTD4, PGE2, bradykinin, and Evans blue dye were purchased from Sigma Chemical Co. (St. Louis, MO); and all other chemicals were obtained from Wako Pure Chemicals (Osaka, Japan) and Nacalai Tesque (Kyoto, Japan).

Animals
Specific, pathogen-free male Hartley strain guinea pigs, with 400–550 g body weights, were purchased from Kyudo Corp. (Kumamoto, Japan). They were maintained in the Center for Animal Resources and Development, Kumamoto University (Japan). The animal experiments were performed under the supervision of the Ethics Committee for Animal Experiments, Kumamoto University.

Preparation of leukocytotic guinea pigs
The leukocytotic guinea pigs were prepared by a daily i.p. injection of G-CSF solution, which was prepared daily by adding sterilized, distilled water to a bottle containing freeze-dried G-CSF and salts, making a concentration of 100 µg/ml G-CSF in physiological saline. The G-CSF solution was administered i.p. once a day for 3–11 days at a dose of 100 µg/kg/day. The numbers of total leukocytes and of PMNs in the peripheral blood were counted before (Day 0) and on Days 3, 7, 9, and 11 of the G-CSF administration using the Turk staining method. To confirm the leukocytosis of neutrophil granulocytes, we prepared blood-smear samples, stained with Giemsa’s solution and analyzed microscopically.

Preparation of leukocytopenic guinea pigs
Circulating PMNs were depleted from guinea pigs as described previously [7 ]. In brief, cyclophosphamide was i.p.-injected at doses of 100 mg/kg and 50 mg/kg, 5 days and 1 day before the day of the permeability experiment, respectively. The numbers of total leukocytes and PMNs in peripheral blood were counted before the cyclophosphamide administrations and on the day of the permeability experiment, using the Turk staining method.

Preparation of antiplatelet antiserum and thrombocytopenic guinea pigs
Antiguinea pig platelet rabbit antiserum (APS) was prepared according to the method of Sanjar et al. [15 ]. Briefly, guinea pig platelets, prepared from blood, obtained by cardiac puncture with a 3.8% citrate buffer (1/10 v/v), were lysed by five cycles of freezing and thawing and then mixed with Freund’s complete adjuvant at 1-to-1 vol to prepare emulsion, which was injected into the four footpads of a rabbit. Booster injections of the platelet emulsion with Freund’s incomplete adjuvant were given i.d. twice at 1-week intervals. After 4 weeks, blood was collected from an ear artery of the rabbit, and the antiserum containing antibodies to the guinea pig platelets was separated and heat-treated at 56°C for 1 h to deactivate complement proteins. As the antiserum contained hemolytic antibodies against guinea pig erythrocytes, the antiserum was absorbed with washed guinea pig erythrocytes. After erythrocytes were removed by centrifugation, the antiserum was aliquoted, stored at –20°C, and used as APS.

The thrombocytopenic guinea pigs were prepared by an i.p. bolus injection (1 ml/kg) of APS. After 20 h, the number of platelets in peripheral blood decreased to 10.2% of that before the APS treatment (before treatment, 337±97x103 platelets/µl; after treatment, 34±24x103 platelets/µl, n=6). The APS treatment did not affect the numbers of erythrocytes and leukocytes (data not shown).

Preparation of zymosan-activated guinea pig plasma (ZAP)
ZAP was prepared as described previously [16 ] and was used as a source of guinea pig C5a. Briefly, heparinized guinea pig plasma, which had been obtained from cardiac blood, was incubated with zymosan (20 mg/ml) in the presence of 10 µM mercaptomethyl-guanidinoethylthiopropanoic acid at 37°C. After 60 min, the zymosan was removed by centrifugation (twice for 20 min at 10,000 rpm). ZAP thus prepared was stored in aliquots at –80°C.

Pretreatments of guinea pigs
The pretreatment of guinea pigs with a bradykinin B2 receptor antagonist, HOE140 [17 , 18 ], was performed as follows. HOE140 solution (50 nmol/ml PBS) was s.c.-injected into guinea pigs at a dose of 10 nmol/kg, 45 min before the Evans blue dye injection. This pretreatment completely inhibited the 100 nM bradykinin-induced plasma extravasation.

The pretreatment of guinea pigs with a cys-LT1 receptor antagonist, pranlukast, was performed as described previously [19 ]. Briefly, pranlukast solution (6 mg/ml) was prepared by dissolving in 0.5% sodium carboxymethylcellulose (CMC) solution just before administration. The pranlukast solution was administrated orally at a dose of 30 mg/kg, 60 min before the Evans blue dye injection. For the late-phase experiment, we additionally administrated 10 mg/kg pranlukast immediately before the Evans blue dye injection.

The pretreatment of guinea pigs with a 5-LO inhibitor, MK-886, was performed as described previously [20 ]. Briefly, MK-886 solution (1 mg/ml) was also prepared by dissolving in 0.5% CMC solution just before administration. The MK-886 solution was administrated orally at a dose of 5 mg/kg, 120 min before the Evans blue dye injection.

Measurement of plasma extravasation
Plasma extravasation was measured using the dye extraction method reported by Udaka et al. [21 ]. Briefly, a 0.1-ml portion of each sample was injected i.d. into the flank of guinea pigs. Samples were injected i.d. as a single set, with a maximum of 10 injected regions in each guinea pig. Evans blue dye (2.5% solution in 0.6% saline) was injected i.v. at a dose of 30 mg/kg. The guinea pigs were killed at 15, 30, or 90 min by exsanguination under ether anesthesia, and skin lesion samples, with a diameter of 14 mm, were punched out. The extravasated Evans blue in each lesion was extracted with formamide (3 ml) for 48–72 h at 60°C, and the optical density of the extract was measured at 620 nm using a spectrophotometer (U-2000A, Hitachi, Japan). Each measured value was converted into an amount of extravasated dye (µg/site).

Preparation of guinea pig anti-OVA IgE antibodies and induction of passive cutaneous anaphylaxis
We prepared alum-precipitated OVA and suspended it at a concentration of 5 mg/ml in 150 mM alum solution. We injected the OVA suspension into femoral muscles of guinea pigs at a dose of 10 mg/animal. Three weeks later, we prepared serum from blood obtained by cardiac puncture and isolated the euglobulin fraction by precipitation with 40% saturation of ammonium sulfate at 4°C. We dissolved it into PBS and removed ammonium sulfate by dialysis against PBS overnight at 4°C. After adjusting the volume to that of the initial serum, we injected 0.1 ml 30-fold- and 100-fold-diluted euglobulin fraction i.d. into guinea pigs, with or without pranlukast pretreatment. Four hours later, we injected the OVA (10 mg/animal) i.v. with the Evans blue dye solution and measured the plasma extravasation for 30 min as described above.

Histological examination
i.d.-Injected skin lesions were excised after the animals were killed by exsanguination under ether anesthesia. After the excised skin pieces were fixed with 10% formalin, they were embedded in paraffin. The 4-µm-thick paraffin sections were stained with H&E. In a morphometric analysis of the infiltrated PMNs, their number was counted at a microscopic high-power field (ocular lens x10, objective lens x40) in five different areas just above the panniculus carnosus muscle. The infiltrated PMN number was expressed as mean ± SD per high-power field.

Statistical analysis
The correlation coefficient was tested by the two-tailed Student’s t-test. The P values less than 0.05 were considered to indicate statistical significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effect of leukocytotic state on C5a-induced plasma extravasation
We have demonstrated that the ZAP-induced plasma extravasation was mediated by two mechanisms, the long-lasting PMN-dependent and the short-lived mast cell-dependent, using cyclophosphamide-pretreated leukocytopenic guinea pigs [7 ]. To investigate the pathophysiological characteristics of the PMN-dependent plasma extravasation, we examined whether systemic leukocytosis enhanced the PMN-dependent response in the local lesion or not.

We prepared leukocytotic guinea pigs by daily i.p. administration of G-CSF. As shown in Table 1 , the administration of G-CSF significantly increased the number of circulating leukocytes in peripheral blood, predominantly PMNs. On Day 0 (before the G-CSF administration), the numbers of total leukocytes and of PMNs were 7551 ± 2616/mm3 and 3155 ± 1434/mm3 (41.8% of the total leukocytes), respectively. On Day 7, the numbers of total leukocytes and of PMNs reached plateau levels, which were 24,298 ± 6531/mm3 and 17,183 ± 5773/mm3 (70.7% of the total leukocytes), respectively. We performed cytological analysis of blood-smear samples stained with Giemsa’s solution. The ratios of neutrophilic, eosinophilic, and basophilic granulocytes in the PMN population on Day 0 were 97.0%, 2.8%, and 0.2%, respectively. After treatment with G-CSF for 9 days, these ratios became 98.6%, 1.1%, and 0.3%, respectively. Among the non-PMN population, the number of lymphocytes and monocytes increased to 1.7 times and 4.9 times by the G-CSF treatment, respectively. The percentages of lymphocytes and monocytes of the total leukocyte count were 65.2% and 8.0% on Day 0 and 16.9% and 6.2% on Day 9, respectively (data not shown).


View this table:
[in this window]
[in a new window]

  		Table 1. Changes in Peripheral Leukocyte Numbers by Pretreatment of Guinea Pigs with rhG-CSF

 
We comparatively examined the time course of ZAP-induced plasma extravasation between normal guinea pigs and the leukocytotic animals, in which the circulating PMN number increased over 20,000/mm3. As shown in Figure 1 , the leukocytotic state significantly augmented the late response from 60 to 150 min after the i.d. injection of ZAP. However, this state greatly increased the variation of intensity of the early-phase until 30 min by an unknown reason, and the expected augmenting effect of the leukocytosis on the early-phase plasma extravasation induced by C5a was not clear.


Figure 1
View larger version (14K):
[in this window]
[in a new window]

  		Figure 1. Time course of ZAP-induced plasma extravasation. Undiluted ZAP (0.1 ml) was i.d.-injected into untreated [{circ}, PMN: 3317±2514/mm3 (a) or 2350±117/mm3 (b)] or G-CSF-pretreated [•, PMN: 26,333±7003/mm3 (a) or 30,102±13,431/mm3 (b)] guinea pigs at a 15-min interval from 45 to 0 min (a) or at a 30-min interval from 120 to 0 min (b). Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 1 min before the final i.d. injection (0 min) of ZAP. The skin lesions with plasma extravasation were harvested 15 min (a) or 30 min (b) after the final i.d. injection. Results are shown as the mean value ± SD of three animals. *, P < 0.05, when comparing the G-CSF-pretreated animals with the untreated animals.

 
We therefore examined the correlation between the number of circulating PMNs and the extent of ZAP-induced plasma extravasation at the late-phase from 60 to 150 min, which consisted of the PMN-dependent response alone. The intensity of ZAP-induced plasma extravasation positively correlated with the number of circulating PMNs (Fig. 2a ). Especially when the circulating PMN number became over 20,000/mm3, the plasma extravasation drastically increased. The same result was observed in the rhC5a injection (Fig. 2b) . Conversely, there was no correlation between the number of non-PMN leukocytes and the ZAP- or rhC5a-induced, late-phase permeability (data not shown). Furthermore, cytological analysis of blood-smear samples stained with Giemsa’s solution indicated that the neutrophilic granulocyte in PMN, but no other leukocyte population or subpopulation, correlated with the permeability intensity (data not shown).


Figure 2
View larger version (15K):
[in this window]
[in a new window]

  		Figure 2. Correlation between intensity of PMN-dependent plasma extravasation and circulating PMN number at (a) ZAP-injection sites and (b) rhC5a-injection sites. {circ}, •, {triangleup}, {blacksquare}, Cases of untreated guinea pigs, G-CSF-pretreated animals, cyclophosphamide-pretreated animals, and cyclophosphamide-pretreated leukocytotic animals induced by G-CSF for 9 days, respectively. Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 60 min after the i.d. injection. The plasma extravasation for 90 min after the Evans blue dye injection was measured. The approximate curves (broken line) and correlation coefficients (R2) are shown.

 
We also examined the effect of systemic leukocytosis on the PMN infiltration in the ZAP- or rhC5a-injected skin lesion histologically. The PMN infiltration was augmented significantly by the G-CSF pretreatment at 75 min after the i.d. injection of ZAP (Fig. 3a 3b and 3e ). Although the rhC5a-induced PMN infiltration was weaker than the ZAP, the same type of result was observed at 150 min after the i.d. injection of rhC5a (Fig. 3c 3d and 3f) . In the ZAP- and rhC5a-injected cases, the infiltrated PMNs were neutrophilic granulocytes but not eosinophilic or basophilic granulocytes.


Figure 3
View larger version (113K):
[in this window]
[in a new window]

  		Figure 3. Histological examination of PMN infiltration induced by i.d. injection of ZAP (a, b) or rhC5a (c, d). Undiluted ZAP (0.1 ml) or rhC5a (1x10–6 M, 0.1 ml) was i.d.-injected into an untreated guinea pig (a, c) or a G-CSF-pretreated animal (b, d). The skin lesions were obtained 75 min (a, b) or 150 min (c, d) after the i.d. injection. The specimens were stained with H&E. Original magnification, x150. Morphometric analysis of the infiltrated PMN number induced by i.d. injection of ZAP (e) or rhC5a (f). The infiltrated PMN number was expressed as mean ± SD per high-power field (ocular lens x10, objective lens x40) of five different areas just above the panniculus carnosus muscle. *, P < 0.001; **, P < 0.005.

 
These results indicate that the systemic granulocytosis augments not only the PMN infiltration but also the plasma extravasation at a local lesion induced by the i.d. injection of C5a.

Effect of permeability factor receptor antagonists on PMN-dependent plasma extravasation in C5a-induced late response
We then examined the molecular mechanism of the PMN-dependent plasma extravasation. First, we investigated whether one of the major permeability factors such as histamine, bradykinin, or cys-LTs participated in the PMN-dependent plasma extravasation by using receptor antagonists of these factors. In this experiment, we initially targeted the late-phase plasma extravasation from 60 to 150 min after the i.d. injection of C5a, composed of the PMN-dependent response alone. As the intensity of the rhC5a-induced late response was weak in the normal animals (Fig. 2b) , we used ZAP instead of rhC5a as the source of C5a.

As shown in Figure 4 , neither simultaneous injection nor systemic administration of an antihistaminic agent, diphenhydramine, affected the ZAP-induced, late-phase plasma extravasation. Similarly, a bradykinin B2 receptor antagonist, HOE140, did not affect the ZAP-induced late response (Fig. 5 ).


Figure 4
View larger version (17K):
[in this window]
[in a new window]

  		Figure 4. Effect of diphenhydramine on late response of ZAP-induced plasma extravasation. (a) Undiluted ZAP (0.1 ml) was i.d.-injected with diphenhydramine (2x10–3 M, 0.1 ml, solid columns) or with saline (open column) into guinea pigs. (b) Diphenhydramine (30 mg/kg, solid column) or saline (open column) was i.p.-injected 60 min before the i.d. sample injection. Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 60 min after the i.d. injection. The plasma extravasation response for 90 min after the Evans blue dye injection was measured. Results are shown as the mean value ± SD of four animals. N.S., Not significant.

 

Figure 5
View larger version (12K):
[in this window]
[in a new window]

  		Figure 5. Effect of bradykinin B2 receptor antagonist, HOE140, on late response of ZAP-induced plasma extravasation. ZAP (0.1 ml) was i.d.-injected into PBS-pretreated (open column) or HOE140-pretreated (solid column) guinea pigs. Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 60 min after the i.d. injection. The plasma extravasation for 90 min after the Evans blue dye injection was measured. Results are shown as the mean value ± SD of three animals.

 
Next, we examined the effect of a cys-LT1 receptor antagonist, pranlukast, on the ZAP-induced, late-phase plasma extravasation. It has been reported that pranlukast is fully effective at 60 min and half effective at 180 min after its oral administration [19 ]. This means that the single oral administration of pranlukast may not cover the later half of the late-phase plasma extravasation induced by the i.d. injection of ZAP. So, we administrated pranlukast twice, at 60 min before and immediately before the Evans blue dye injection. This method completely suppressed the plasma extravasation induced by an i.d. injection of 100 ng/0.1 ml LTD4 with PGE2 at the 15 min before the end of the observation period. This pranlukast treatment significantly suppressed the late-phase plasma extravasation to 28.5% of that of the control guinea pigs (Fig. 6a ).


Figure 6
View larger version (14K):
[in this window]
[in a new window]

  		Figure 6. Effect of cys-LT1 receptor antagonist, pranlukast, or 5-LO inhibitor, MK-886, on ZAP-induced, late-phase plasma extravasation. (a) Pranlukast or vehicle was orally administered twice, 60 min before (30 mg/kg) and just before (10 mg/kg) the Evans blue dye injection. Undiluted ZAP (0.1 ml) was i.d.-injected into vehicle-pretreated (open columns) or pranlukast-pretreated (solid columns) guinea pigs. Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 60 min after the i.d. injection of ZAP. PGE2 (0.1 µg/0.1 ml) or LTD4 (100 ng/0.1 ml) with PGE2 was i.d.-injected 75 min after the Evans blue dye injection (15 min before the sacrifice). The plasma extravasation was measured for 90 min after the Evans blue dye injection. Results are shown as the mean value ± SD of three animals. (b) MK-886 (5 mg/kg) or vehicle was orally administered 120 min before the Evans blue dye injection. Undiluted ZAP (0.1 ml) was i.d.-injected into vehicle-pretreated (open column) or MK-886-pretreated (solid column) guinea pigs. Evans blue dye was injected i.v. 60 min after the i.d. injection of ZAP. The plasma extravasation was measured for 90 min after the Evans blue dye injection. Results are shown as the mean value ± SD of three animals. *, P < 0.005; **, P < 0.05.

 
To confirm that the suppressive effect of the pranlukast treatment was attributed to the inhibition of cys-LTs, we also examined the effect of a 5-LO inhibitor, MK-886, which inhibits cys-LT biosynthesis [22 ], on the late-phase plasma extravasation. The systemic administration of MK-886 also suppressed the ZAP-induced late response down to 51.9% of that of the control guinea pigs (Fig. 6b) . This MK-886 treatment did not affect the plasma extravasation induced by the extrinsic LTD4 injection with PGE2 (data not shown).

These results indicate that the PMN-dependent plasma extravasation would be mediated mainly by cys-LTs but not by histamine or bradykinin.

Effect of permeability factor receptor antagonists on C5a-induced, early-phase plasma extravasation
The C5a-induced, early-phase plasma extravasation is composed of two mechanisms, one being PMN-dependent and the other, histamine-dependent, as we described previously [7 ]. To confirm the ratio of the PMN-dependent response to the total plasma extravasation, we prepared leukocytopenic guinea pigs by the cyclophosphamide administration. When the circulating PMNs were depleted by the cyclophosphamide pretreatment, the rhC5a-induced, early response within 30 min after the i.d. injection was suppressed to 62.8% of the untreated guinea pigs (Fig. 7 ). After a simultaneous injection of the antihistaminic agent, diphenhydramine, with rhC5a, the early-phase plasma extravasation was suppressed to 27.1% of the rhC5a alone. Furthermore, when diphenhydramine was simultaneously injected with rhC5a into the cyclophosphamide-pretreated animals, the early-phase plasma extravasation was reduced significantly to 7.0% of the rhC5a-induced plasma extravasation of untreated animals. As the extent of the remaining plasma extravasation was equivalent to that induced by diphenhydramine (negative control), these results suggested that the rhC5a-induced, early-phase plasma extravasation was suppressed completely by the combined treatment with cyclophosphamide and diphenhydramine. Furthermore, these results indicated again that ~40% and 60% of the rhC5a-induced, early-phase response were mediated by the PMN-dependent and histamine-dependent mechanisms, respectively.


Figure 7
View larger version (16K):
[in this window]
[in a new window]

  		Figure 7. Effect of diphenhydramine on early response of rhC5a-induced plasma extravasation. Diphenhydramine (2x10–3 M, 0.1 ml), rhC5a (1x10–6 M, 0.1 ml), rhC5a with diphenhydramine, histamine (1 µg/0.1 ml), and histamine with diphenhydramine were i.d.-injected into untreated (open columns) or cyclophosphamide-pretreated (solid columns) guinea pigs. Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 15 min before the i.d. injection. The plasma extravasation was measured for 30 min after the i.d. injection. Results are shown as the mean value ± SD of three animals. *, P < 0.05; **, P < 0.01.

 
We then examined the contribution of cys-LTs in the C5a-induced, early-phase plasma extravasation. As shown in Figure 8 , the pretreatment with pranlukast suppressed the rhC5a-induced, early-phase plasma extravasation to 63.0% of the control. A simultaneous injection of diphenhydramine with rhC5a, the early-phase plasma extravasation was suppressed to 35.5% of the rhC5a alone. Furthermore, when diphenhydramine was simultaneously injected with rhC5a into the pranlukast-pretreated animals, the early-phase plasma extravasation was reduced significantly to 13.1% of the rhC5a-induced plasma extravasation of the control animals. The remaining extent of extravasation was almost equivalent to that induced by diphenhydramine or PGE2 (negative controls). These results suggested that most of the rhC5a-induced, early-phase plasma extravasation was suppressed by the combined treatment with pranlukast and diphenhydramine. Furthermore, the pranlukast pretreatment did not suppress the ZAP-induced, early plasma extravasation in the cyclophosphamide-pretreated leukocytopenic guinea pigs (Fig. 9 ). These results indicated again that most of the PMN-dependent plasma extravasation would be mediated by cys-LTs.


Figure 8
View larger version (17K):
[in this window]
[in a new window]

  		Figure 8. Effect of pranlukast and diphenhydramine on early response of rhC5a-induced plasma extravasation. Diphenhydramine (2x10–3 M, 0.1 ml), rhC5a (1x10–6 M, 0.1 ml), rhC5a with diphenhydramine, PGE2 (0.1 µg/0.1 ml), and LTD4 (100 ng/0.1 ml) with PGE2 were i.d.-injected into vehicle-pretreated (open columns) or pranlukast-pretreated (solid columns) guinea pigs. Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 15 min before the i.d. injection. The plasma extravasation was measured for 30 min after the i.d. injection. Results are shown as the mean value ± SD of five animals. *, P < 0.05; **, P < 0.005.

 

Figure 9
View larger version (15K):
[in this window]
[in a new window]

  		Figure 9. Effect of pranlukast on ZAP-induced, early-phase plasma extravasation in granurocytopenic guinea pigs. Undiluted ZAP (0.1 ml) was i.d.-injected into vehicle-pretreated guinea pigs (open column) or a pranlukast-pretreated guinea pig (solid column). In these animals, PMNs had been depleted by the cyclophosphamide pretreatment. Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 15 min before the i.d. injection. The plasma extravasation for 60 min after the i.d. injection was measured. Results are shown as the mean value ± SD of three animals for vehicle and as the value of a single animal for pranlukast.

 
We confirmed these findings using the 5-LO inhibitor MK-886. The pretreatment with MK-886 reduced the ZAP-induced, early-phase plasma extravasation to 57.3%, as in the case of pranlukast administration (Fig. 10 ). In contrast to this, the pretreatment with HOE140 did not affect the rhC5a-induced nor ZAP-induced, early-phase plasma extravasation, as in the case of the ZAP-induced, late-phase response (data not shown).


Figure 10
View larger version (33K):
[in this window]
[in a new window]

  		Figure 10. Effect of MK-886 on early response of ZAP-induced plasma extravasation. Undiluted ZAP (0.1 ml), PGE2 (0.1 µg/0.1 ml), and LTD4 (100 ng/0.1 ml) with PGE2 were i.d.-injected into vehicle-pretreated (open columns) or pranlukast-pretreated (solid columns) or MK-886-pretreated (hatched columns) guinea pigs. Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 15 min before the i.d. injection. The plasma extravasation was measured for 60 min after the i.d. injection. Results are shown as the mean value ± SD of five animals. *, P < 0.01, compared with ZAP of vehicle-pretreated guinea pigs.

 
These results strongly indicate that cys-LTs mediate the PMN-dependent plasma extravasation.

Effect of cys-LT blocking on PMN extravasation
To examine whether the inhibition of the PMN-dependent plasma extravasation affected the PMN infiltration, we prepared histologic tissue specimens. Histologically and morphometrically, the pranlukast or MK-886 pretreatments did not affect the intensity of ZAP-induced PMN infiltration (Fig. 11 ). These observations suggest that the PMN-dependent and cys-LT-mediated plasma extravasation is a separate phenomenon from the transendothelial PMN migration.


Figure 11
View larger version (134K):
[in this window]
[in a new window]

  		Figure 11. Histological examination of PMN infiltration induced by i.d. injection of ZAP. Undiluted ZAP (0.1 ml) was i.d.-injected into untreated (a), pranlukast-pretreated (b), or MK-886-pretreated (c) guinea pigs. The skin lesions were obtained 120 min after the i.d. injection. The specimens were stained with H&E. Original magnification, x150. Morphometric analyses of the infiltrated PMN numbers were performed (d). The infiltrated PMN numbers were expressed as mean ± SD per high-power field (ocular lens x10, objective lens x40) of five different areas just above the panniculus carnosus muscle.

 
No effect of cys-LT1 receptor antagonist on mast cell-dependent plasma extravasation
Mast cells and macrophages are generally considered to be cys-LT producers [23 ]. However, monocytes/macrophages can be discarded from being the cellular source of cys-LTs causing plasma extravasation, as the monocyte infiltration does not accompany the plasma extravasation [7 ]. So, we examined whether mast cell degranulation accompanies the release of cys-LTs. To induce skin mast cell degranulation, we used two different methods. One was by i.d. injection of a degranulation-inducing reagent, compound 48/80, and the other was obtained by passive cutaneous anaphylaxis, in which the IgE antibody/Fc{epsilon} receptor (Fc{epsilon}R)-mediated degranulation was induced using OVA as the antigen. As shown in Figure 12 , pranlukast pretreatment did not affect the plasma extravasation induced by either method, and in both cases, it was suppressed by diphenhydramine. The mast cells were thought to release histamine but not cys-LTs upon the stimulation of degranulation in the guinea pig skin. These results strongly suggest that the mast cells are not the source of cys-LTs, which mediate the PMN-dependent plasma extravasation.


Figure 12
View larger version (15K):
[in this window]
[in a new window]

  		Figure 12. Effect of pranlukast on mast cell degranulation. (a) i.d. injection of a degranulation-inducing reagent, compound 48/80. Histamine (1 µg/0.1 ml), histamine with diphenhydramine (2x10–3 M, 0.1 ml), compound 48/80 (10 µg/0.1 ml), and compound 48/80 with diphenhydramine were i.d.-injected into vehicle-pretreated (open columns) or pranlukast-pretreated (solid columns) guinea pigs. Evans blue dye was i.v-injected (30 mg/kg 2.5% solution) 15 min before the i.d. injection. The plasma extravasation was measured for 30 min after the i.d. injection. Results are shown as the mean value ± SD of five animals. (b) Passive cutaneous anaphylaxis, which causes the IgE antibody/Fc{epsilon}R-mediated degranulation. Anti-OVA euglobulin fraction (30-fold and 100-fold dilution, 0.1 ml) was i.d.-injected into vehicle-pretreated (open columns) or pranlukast-pretreated (solid columns) guinea pigs. Four hours later, an OVA (10 mg/animal) and Evans blue dye mixture was i.v.-injected, and the plasma extravasation was measured for 30 min as described above. Results are shown as the mean value ± SD of three animals.

 
No influence of platelet depletion on pranlukast-inhibitable plasma extravasation induced by C5a injection
A cys-LT, LTC4, is produced from LTA4 and glutathione under catalysis by LTC4 synthase, a GST. PMNs have a capacity to produce LTA4 but not LTC4 because of lacking the enzyme [24 ]. An alternative way to produce LTC4 is a cooperative work between PMN and another cell type, which possesses LTC4 synthase. Candidates of the cooperator cell would be platelets [25 ], pericytes [26 ], and endothelial cells [27 , 28 ]. Therefore, we depleted platelets from guinea pigs and measured the C5a-induced plasma extravasation under the presence or the absence of pranlukast. However, the pranlukast-inhibitable plasma extravasation induced by rhC5a was not influenced by platelet depletion (Fig. 13 ). The results obtained in the platelet-depleted animals were almost the same as those in the normal animals, as shown in Figure 8 . These results strongly suggest that platelets do not participate in the production of cys-LTs mediating the PMN-dependent plasma extravasation.


Figure 13
View larger version (17K):
[in this window]
[in a new window]

  		Figure 13. No influence of platelet depletion to the suppressive effect of pranlukast on the early response of rhC5a-induced plasma extravasation. The thrombocytopenic guinea pigs were prepared by an i.p. bolus injection (1 ml/kg) of APS. After 20 h, the number of platelets in peripheral blood decreased to 10.2% of that before the APS treatment (before treatment, 337±97x103 platelets/µl; after treatment, 34±24x103 platelets/µl, n=6). These guinea pigs were divided into two groups (n=3 in each groups). One group was treated with pranlukast, and the other was with the vehicle buffer as in Figure 6a . LTD4 (100 ng/0.1 ml) with PGE2 (0.1 µg/0.1 ml), histamine (1 µg/0.1 ml) with or without diphenhydramine (2x10–3 M, 0.1 ml), and rhC5a (1x10–6 M, 0.1 ml) with or without diphenhydramine were i.d.-injected into the vehicle-pretreated (open columns) or pranlukast-pretreated (solid columns) thrombocytopenic guinea pigs. Evans blue dye was i.v.-injected (30 mg/kg 2.5% solution) 15 min before the i.d. injection. The plasma extravasation was measured for 30 min after the i.d. injection. Results are shown as the mean value ± SD of three animals. *, P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we demonstrated that the systemic granulocytosis induced by the G-CSF administration augmented not only the number of infiltrated PMNs but also the extent of PMN-dependent plasma extravasation in the C5a-injected lesion. Using a carrageenin-induced rat pleurisy model, Ogino et al. [29 ] observed that the increased number of circulating PMNs induced by G-CSF administration enhanced migration of PMNs into the pleural cavities and increased the production of pleural fluids. Their observations, as well as ours, indicate that the systemic leukocytosis in the acute inflammatory reaction augments the local extravascular mobilizations of the plasma components via the PMN-dependent plasma extravasation mechanism. This primary role of the acute inflammatory reaction seems to be a reasonable host defense response.

However, a remarkable plasma extravasation occurred when the number of circulating PMNs exceeded 20,000/mm3 by the G-CSF pretreatment. This suggests that an excessive systemic leukocytosis would induce a hyperinflammatory reaction at the local site. G-CSF is commonly used for neutropenic patients after cytotoxic chemotherapy for various malignant tumors to recover the number of circulating PMNs [30 31 32 33 ]. However, there are some clinical reports about the pulmonary toxicity occurring after G-CSF therapy combined with bleomycin [34 35 36 37 38 ]. A combined application of amphotericin B and granulocyte transfusions may also cause a similar pulmonary injury [39 ]. These clinical reports suggest that the extensive, systemic leukocytosis might cause a hyperinflammatory response in the lungs. We assume that the augmentation of the PMN-dependent plasma extravasation by the systemic leukocytosis would participate in these cases. Therefore, when G-CSF is administrated to neutropenic patients, it is important to monitor the leukocyte number of the patients so they do not exceed the normal range.

The mechanisms of the PMN-dependent plasma extravasation have not yet been clarified. In the rat mesenteric window, disruption of the endothelial actin cytoskeleton was observed within 3 min after the leukocyte adhesion to endothelial cells, resulting in plasma extravasation [40 ]. This report suggests the importance of PMN adherence to endothelial cells in the PMN-dependent plasma extravasation. As for the mechanisms responsible for the disruption of the endothelial actin cytoskeleton produced by PMN adhesion to endothelial cells, we consider two possibilities: induction of intracellular signal transduction by adhesion molecule engagement, thereby remodeling the actin cytoskeleton in the endothelial cells, and autocrine or paracrine/juxtacrine mechanism via a bioactive molecule with a permeability-enhancing effect, released by the PMNs or by the endothelial cells upon the adhesion between them. Although some reports regarding CD18 (β2 integrin) and/or vascular endothelial-cadherin/catenin complex support the first mechanism [41 , 42 ], they do not rule out the second possibility. Gautam et al. [43 ] recently demonstrated that azurocidin released from PMNs upon adhesion to endothelial cells via CD18 caused the plasma leakage through an endothelial monolayer in vitro. This is a unique observation, supporting the paracrine or juxtacrine mechanism. However, this observation has not yet been confirmed in vivo. Contrary to this, in this study, we have demonstrated here in vivo that the PMN-dependent plasma extravasation would be mediated mainly by cys-LTs.

cys-LTs are major inflammatory mediators produced via the 5-LO pathway, which is present in mast cells [44 ]. However, cutaneous mast cells failed to produce cys-LTs in our three different guinea pig models of passive cutaneous anaphylaxis, C5a stimulation, and compound 48/80-induced degranulation. This is consistent with a previous report about human mast cell subpopulations, where cutaneous mast cells, which possess tryptase and chymase, liberate histamine but not cys-LTs in response to various stimuli, and the major subpopulation of lung mast cells, which possess only tryptase, liberates cys-LTs as well as histamine when stimulated [45 ]. Contrary to our results, passive cutaneous anaphylaxis in the ear dermis of the cys-LT1 receptor-deficient mouse was reportedly suppressed [14 ]. We do not know the reason why the same IgE antibody/Fc{epsilon}R-mediated mast cell response differed between the guinea pig flank skin and the mouse ear dermis. It may be a result of a species difference between guinea pig and mouse or a result of a difference of mast cell subtypes between flank skin and ear dermis.

In our guinea pig model, the lack of cys-LT-generating capacity of cutaneous mast cells strongly suggests that PMNs themselves would produce cys-LTs and cause the plasma extravasation. Indeed, there is a report that PMNs produce LTA4 from arachidonic acid by 5-LO [46 ]. Amounts of LTA4 released from PMNs peaked at 2 min after stimulation in vitro. However, PMNs cannot convert LTA4 to LTC4 as a result of a lack of LTC4 synthase [24 ]. Recent in vitro studies have demonstrated a transcellular biosynthesis of LTC4 among PMNs and platelets [25 ], pericytes [26 ], or endothelial cells [27 , 28 ]. As these cells have LTC4 synthase and glutathione, they can convert the PMN-derived LTA4 to LTC4. In the present study, the thrombocytopenic state did not influence the pranlukast-inhibitable plasma extravasation induced by the rhC5a injection. We, therefore, conclude that platelets do not interact with PMNs in the transcellular biosynthesis of cys-LTs associated with the PMN infiltration. The plasma extravasation induced by a cys-LT injection occurs at the postcapillary venule, where the leukocyte adhesion to endothelial cells takes place [47 ]. Postcapillary venules have pericytes and modulate the vascular contraction and permeability [48 ]. Therefore, the remaining possibilities are that PMNs would contact with endothelial cells or with pericytes during extravasation and would then produce cys-LTs transcellularly. To clarify whether endothelial cells or pericytes are the source of cys-LTs, it would be necessary to histologically examine the cellular localization of the LTC4 synthase and glutathione. However, there is neither an anti-LTC4 synthase antibody nor a histochemical reagent applicable in the guinea pig. In terms of the time course, when the plasma extravasation occurred within a few minutes after an i.d. injection of rhC5a, PMNs were still present in the vascular lumen in contact with endothelial cells [7 ]. This suggests that the most possible source of the cys-LTs would be endothelial cells but not pericytes. Zahler et al. [49 ] have demonstrated a new mechanism of PMN-endothelial communication in which bidirectional gap junctions coupling PMNs and endothelial cells are formed during the transendothelial migration of PMNs in vitro. Therefore, we speculate that the PMN-endothelial gap junctions would provide a suitable condition for the transcellular biosynthesis of cys-LTs in vivo. Furthermore, pranlukast pretreatment did not affect the C5a-induced PMN infiltration, suggesting that the cys-LT biosynthesis by PMN-endothelial cell communication and the PMN extravasation are independent phenomena.

We conclude that the PMN-dependent plasma protein extravasation is mainly mediated by cys-LTs, which would be synthesized transcellularly via the PMN-endothelial cell communications. The biological significance of this mechanism is its role in the augmentation of the local plasma extravasating reaction by the systemic leukocytosis in the acute inflammation.


   ACKNOWLEDGEMENTS
 
We thank Shionogi Pharmaceutical Corp., Ono Pharmaceutical Corp., and Merck Frosst Canada and Co. for providing us important reagents. We also thank Ms. T. Kubo for her technical assistance in the histological preparations. We appreciate Dr. Ivette Revollo’s advice on the use of English in our manuscript.

Received August 31, 2005; revised June 26, 2006; accepted June 30, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Issekutz, A. C. (1981) Effect of vasoactive agents on polymorphonuclear leukocyte emigration in vivo Lab. Invest. 45,234-240
  2. Issekutz, A. C. (1981) Vascular responses during acute neutrophilic inflammation: their relationship to in vivo neutrophil emigration Lab. Invest. 45,435-441
  3. Wedmore, C. V., Williams, T. J. (1981) Control of vascular permeability by polymorphonuclear leukocytes in inflammation Nature 289,646-650[CrossRef][Medline]
  4. Jose, P. J., Forrest, M. J., Williams, T. J. (1981) Human C5a des arg increases vascular permeability J. Immunol. 127,2376-2380[Abstract]
  5. Yancey, K. B., Bielory, L., Wright, R., Young, N., Frank, M. M., Lawley, T. J. (1987) Patients with bone marrow failure demonstrate decreased cutaneous reactivity to human C5a J. Invest. Dermatol. 88,388-392[CrossRef][Medline]
  6. Williamson, L. M., Sheppard, K., Davies, J. M., Fletcher, J. (1986) Neutrophils are involved in the increased vascular permeability produced by activated complement in man Br. J. Haematol. 64,375-384[Medline]
  7. Tokita, K., Yamamoto, T. (2004) Differential role of neutrophils and monocytes during subcutaneous plasma extravasation Lab. Invest. 84,1174-1184[CrossRef]
  8. El-Lati, S. G., Dahinden, C. A., Church, M. K. (1994) Complement peptides C3a- and C5a-induced mediator release from dissociated human skin mast cells J. Invest. Dermatol. 102,803-806[CrossRef][Medline]
  9. Lum, H., Malik, A. B. (1996) Mechanisms of increased endothelial permeability Can. J. Physiol. Pharmacol. 74,787-800[CrossRef][Medline]
  10. Joris, I., Majno, G., Corey, E. J., Lewis, R. A. (1987) The mechanism of vascular leakage induced by leukotriene E4: endothelial contraction Am. J. Pathol. 126,19-24[Abstract]
  11. Feletou, M., Bonnardel, E., Canet, E. (1996) Bradykinin and changes in microvascular permeability in the hamster cheek pouch: role of nitric oxide Br. J. Pharmacol. 118,1371-1376
  12. Befus, A. D., Mowat, C., Gilchrist, M., Hu, J., Solomon, S., Bateman, A. (1999) Neutrophil defensins induce histamine secretion from mast cell: mechanisms of action J. Immunol. 163,947-953[Abstract/Free Full Text]
  13. Figueroa, C. D., Henderson, L. M., Kaufmann, J., De La Cadena, R. A., Colman, R. W., Muller-Esterl, W., Bhoola, K. D. (1992) Immunovisualization of high (HK) and low (LK) molecular weight kininogens on isolated human neutrophils Blood 79,754-759[Abstract/Free Full Text]
  14. Maekawa, A., Austen, K. F., Kanaoka, Y. (2002) Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses J. Biol. Chem. 277,20820-20824[Abstract/Free Full Text]
  15. Sanjar, S., Kristersson, A., Mazzoni, L., Morley, J., Schaeublin, E. (1990) Increased airway reactivity in the guinea-pig follows exposure to intravenous isoprenaline J. Physiol. 425,43-54[Abstract/Free Full Text]
  16. Horino, K., Nishiura, H., Ohsako, T., Shibuya, Y., Hiraoka, T., Kitamura, N., Yamamoto, T. (1998) A monocyte chemotactic factor, S19 ribosomal protein dimer, in phagocytic clearance of apoptotic cells Lab. Invest. 78,603-617[Medline]
  17. Hock, F. J., Wirth, K., Albus, U., Linz, W., Gerhards, H. J., Wiemer, G., Henke, St., Breipohl, G., Konig, W., Scholkens, B. A. (1991) HOE140, a new potent and long acting bradykinin-antagonist: in vitro studies Br. J. Pharmacol. 102,769-773[Medline]
  18. Wirth, K., Hock, F. J., Albus, U., Linz, W., Alpermann, H. G., Anagnostopoulos, H., Henke, St., Breipohl, G., Konig, W., Knolle, J., Scholkens, B. A. (1991) HOE140, a new potent and long acting bradykinin-antagonist: in vivo studies Br. J. Pharmacol. 102,774-777[Medline]
  19. Nakagawa, N., Obata, T., Kobayashi, T., Okada, Y., Nambu, F., Terawaki, T., Aishita, H. (1992) In vivo pharmacologic profile of ONO-1078: a potent, selective and orally active peptide leukotriene (LT) antagonist Jpn. J. Pharmacol. 60,217-225[Medline]
  20. Gillard, J., Ford-Hutchinson, A. W., Chan, C., Charleson, S., Denis, D., Foster, A., Fortin, R., Leger, S., McFarlane, C. S., Morton, H., et al (1989) L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor Can. J. Physiol. Pharmacol. 67,456-464[Medline]
  21. Udaka, K., Takeuchi, Y., Movat, H. Z. (1970) Simple method for quantitation of enhanced vascular permeability Proc. Soc. Exp. Biol. Med. 133,1384-1387[Medline]
  22. Rouzer, C. A., Ford-Hutchinson, A. W., Morton, H. E., Gillard, J. W. (1990) MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes J. Biol. Chem. 265,1436-1442[Abstract/Free Full Text]
  23. Henderson, W. R., Jr (1994) The role of leukotrienes in inflammation Ann. Intern. Med. 121,684-697[Abstract/Free Full Text]
  24. Lam, B. K., Austen, K. F. (2002) Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes Prostaglandins Other Lipid Mediat. 68-69,511-520
  25. Maclouf, J. A., Murphy, R. C. (1988) Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets: a potential cellular source of leukotriene C4 J. Biol. Chem. 263,174-181[Abstract/Free Full Text]
  26. Mcmurdo, L., Stephenson, A. H., Baldassare, J. J., Sprague, R. S., Lonigro, A. J. (1998) Biosynthesis of sulfidopeptide leukotrienes via the transfer of leukotriene A4 from polymorphonuclear cells to bovine retinal pericytes J. Pharmacol. Exp. Ther. 285,1255-1259[Abstract/Free Full Text]
  27. Feinmark, S. J., Cannon, P. J. (1986) Endothelial cell leukotriene C4 synthesis results from intercellular transfer of leukotriene A4 synthesized by polymorphonuclear leukocytes J. Biol. Chem. 261,16466-16472[Abstract/Free Full Text]
  28. Claesson, H. E., Haeggstrom, J. (1988) Human endothelial cells stimulate leukotriene synthesis and convert granulocyte released leukotriene A4 into leukotrienes B4, C4, D4 and E4 Eur. J. Biochem. 173,93-100[Medline]
  29. Ogino, M., Majima, M., Kawamura, M., Hatanaka, K., Saito, M., Harada, Y., Katori, M. (1996) Increased migration of neutrophils to granulocyte-colony stimulating factor in rat carrageenin-induced pleurisy: roles of complement, bradykinin, and inducible cyclooxygenase-2 Inflamm. Res. 45,335-346[CrossRef][Medline]
  30. Bronchud, M. H., Scarffe, J. H., Thatcher, N., Crowther, D., Souza, L. M., Anton, N. K., Testa, N. G., Dexter, T. M. (1987) Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer Br. J. Cancer 56,809-813[Medline]
  31. Morstyn, G., Campbell, L., Souza, L. M., Alton, N. K., Keech, J., Green, M., Sheridan, W., Metcalf, D., Fox, R. (1988) Effect of granulocyte-colony stimulating factor on neutropenia induced by cytotoxic chemotherapy Lancet 1,667-672[CrossRef][Medline]
  32. Gabrilove, J. L., Jakubowski, A., Scher, H., Sternberg, C., Wong, G., Grous, J., Yagoda, A., Fain, K., Moore, M. A. S., Clarkson, B., Oettgen, H. F., Alton, K., Welte, K., Souza, L. (1988) Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium N. Engl. J. Med. 318,1414-1422[Abstract]
  33. Gabrilove, J. L., Jakubowski, A., Fain, K., Grous, J., Scher, H., Sternberg, C., Yagoda, A., Clarkson, B., Bonilla, M. A., Oettgen, H. F., Alton, K., Boone, T., Altrock, B., Welte, K., Souza, L. (1988) Phase I study of granulocyte colony-stimulating factor in patients with transitional cell carcinoma of the urothelium J. Clin. Invest. 82,1454-1461[Medline]
  34. Matthews, J. H. (1993) Pulmonary toxicity of ABVD chemotherapy and G-CSF in Hodgkin’s disease: possible synergy Lancet 342,988[Medline]
  35. Lei, K. I. K., Leung, W. T., Johnson, P. J. (1994) Serious pulmonary complications in patients receiving recombinant granulocyte colony-stimulating factor during BACOP chemotherapy for aggressive non-Hodgkin’s lymphoma Br. J. Cancer 70,1009-1013[Medline]
  36. Dirix, L. Y., Schrijvers, D., Druwe, P., Van Den Brande, J., Verhoeven, D., Van Oosterom, A. T. (1994) Pulmonary toxicity and bleomycin Lancet 344,56[Medline]
  37. Schilero, G. J., Oropello, J., Benjamin, E. (1995) Impairment in gas exchange after granulocyte colony stimulating factor (G-CSF) in a patient with the adult respiratory distress syndrome Chest 107,276-278[Medline]
  38. Katoh, M., Takada, M., Nakayama, M., Umeda, M. (1996) Pulmonary toxicity during granulocyte colony stimulating factor administration and neutrophils Chest 110,576-577
  39. Wright, D. G., Robichaud, K. J., Pizzo, P. A., Deisseroth, A. B. (1981) Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions N. Engl. J. Med. 304,1185-1189[Abstract]
  40. Valeski, J.E., Baldwin, A.L. (1999) Effect of early transient adherent leukocytes on venular permeability and endothelial actin cytoskeleton Am. J. Physiol. 277,H569-H575[Medline]
  41. Teixeira, M. M., Reynia, S., Robinson, M., Shock, A., Williams, T. J., Williams, F. M., Rossi, A. G., Hellewell, P. G. (1994) Role of CD18 in the accumulation of eosinophils and neutrophils and local oedema formation in inflammatory reactions in guinea-pig skin Br. J. Pharmacol. 111,811-818
  42. Del Maschio, A., Zanetti, A., Corada, M., Rival, Y., Ruco, L., Lampugnani, M. G., Dejana, E. (1996) Polymorphonuclear leukocyte adhesion triggers the disorganization of endothelial cell-to-cell adherens junctions J. Cell Biol. 135,497-510[Abstract/Free Full Text]
  43. Gautam, N., Olofsson, A. M., Herwald, H., Iversen, L. F., Lundgren-Akerlund, E., Hedqvist, P., Arfors, K. E., Flodgaard, H., Lindbom, L. (2001) Heparin-binding protein (HBP/CAP37): a missing link in neutrophil-evoked alteration of vascular permeability Nat. Med. 7,1123-1127[CrossRef][Medline]
  44. Reid, G. K., Kargman, S., Vickers, P. J., Mancini, J. A., Leveille, C., Ethier, D., Miller, D. K., Gillard, J. W., Dixon, R. A. F., Evans, J. F. (1990) Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis J. Biol. Chem. 265,19818-19823[Abstract/Free Full Text]
  45. Oskeritzian, C. A., Zhao, W., Min, H. K., Xia, H. Z., Pozaz, A., Kiev, J., Schwartz, L. B. (2005) Surface CD88 functionally distinguishes the MCTC from the MCT type of human lung mast cell J. Allergy Clin. Immunol. 115,1162-1168[CrossRef][Medline]
  46. Sun, F. F., McGuire, J. C. (1984) Metabolism of arachidonic acid by human neutrophils: characterization of the enzymatic reactions that lead to the synthesis of leukotriene B4 Biochim. Biophys. Acta 794,56-64[Medline]
  47. Dahlen, S. E., Bjork, J., Hedqvist, P., Arfors, K. E., Hammarstrom, S., Lindgren, J. A., Samuelsson, B. (1981) Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response Proc. Natl. Acad. Sci. USA 78,3887-3891[Abstract/Free Full Text]
  48. Shepro, D., Morel, N. M. L. (1993) Pericyte physiology FASEB J. 7,1031-1038[Abstract]
  49. Zahler, S., Hoffmann, A., Gloe, T., Pohl, U. (2003) Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration J. Leukoc. Biol. 73,118-126[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J BiochemHome page
Y. Oda, K. Tokita, Y. Ota, Y. Li, K. Taniguchi, N. Nishino, K. Takagi, T. Yamamoto, and H. Nishiura
Agonistic and Antagonistic Effects of C5a-Chimera Bearing S19 Ribosomal Protein Tail Portion on the C5a Receptor of Monocytes and Neutrophils, Respectively
J. Biochem., September 1, 2008; 144(3): 371 - 381.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.0805488v1
80/6/1308    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tokita, K.