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Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast with PAR1, very little is known about
the physiological and pathophysiological role of
PAR2. Previous studies have shown that
PAR2 activation caused relaxation of rat aorta rings and that
this effect was dependent on the integrity of the endothelium and was
mediated by the production of nitric oxide (10, 14). In
rats or in mice in which the gene for PAR1 has
been deleted, the i.v. injection of a
PAR2-activating peptide has been shown to produce
a marked fall in blood pressure (15, 16, 17). The
up-regulation of PAR2 mRNA in cultured
endothelial cells after the addition of IL-1
, TNF-, or LPS
constitutes one of the first arguments in favor of a possible role for
PAR2 during inflammation (18).
Moreover, we showed in a recent study that the injection of selective
PAR2-APs (SL-NH2 and
Tc-NH2) into the rat paw can cause an acute
inflammatory response characterized by edema and granulocyte
infiltration (19).
Polymorphonuclear leukocytes are key cellular mediators in host defense against injury and infection. The ability of these cells to recognize the vascular endothelium proximal to sites of infection, to adhere to the vessel wall, and to transmigrate into the site of the wound represents one of the early steps of the inflammatory reaction. Leukocyte rolling, adhesion, extravasation, and migration to the inflammatory site allow phagocytes to get to their target, thereby providing a defense against invading pathogens. From the studies summarized above, it appears that PAR2 activation can be hypothesized to play a role in inflammatory reactions by causing vascular changes and granulocyte infiltration. It has been shown that PAR2 is highly expressed both on the endothelium and on leukocytes, in particular neutrophils (20). However the effect of PAR2 activation on leukocyte-endothelial cell interactions has not been reported to date. Therefore, we wished to determine whether PAR2 activation might induce changes in leukocyte rolling, adhesion, and extravasation. Using intravital video microscopy, the effects of two PAR2 agonists, SL-NH2 and Tc-NH2, were tested on mesenteric venule diameter and leukocyte rolling and adhesion. In addition, the ability of PAR2 activation to recruit polymorphonuclear leukocytes was tested by injecting a selective PAR2-AP i.p. and monitoring the extravasation of leukocytes into the peritoneal cavity. Finally, the role of mast cells and the role of platelet-activating factor (PAF) in the PAR2-AP-induced increase in leukocyte adherence, rolling, and extravasation were investigated.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male Wistar rats (175–200 g) were obtained from Charles River Breeding Farms (Montreal, QC, Canada). Animals had free access to food and water and were housed under constant temperature (22°C) and photoperiod (12-h light-dark cycle). All experimental procedures were approved by the Animal Care Committee of the University of Calgary and were performed in accordance with the guidelines established by the Canadian Council on Animal Care.
Leukocyte rolling adherence in vivo
Rats (n = 5 or 6 per group) were fasted a minimum of 15 h before the beginning of the experiment. The animals were anesthetized with sodium pentobarbital (60 mg/kg i.p.) and a midline abdominal incision was made. Rats were then placed in a supine position on an adjustable Plexiglas microscope stage. A segment of the midjejunum was exteriorized through the abdominal incision, and the mesentery was prepared for in vivo microscopic observation, as previously described (21). Briefly, the mesentery was draped over an optically clear viewing pedestral that allows for transillumination of a 2-cm2 segment of mesenteric tissue. The temperature of the pedestral was maintained at 37°C with a constant temperature circulator. The exposed bowel was covered with saline-soaked gauze to minimize tissue dehydration, and the mesentery was superfused with warm (37°C) bicarbonate-buffered saline, pH 7.4. The mesenteric microcirculation was observed using a microscope (Nikon optiphot-2) with a x25 objective lens (Leiz Wetzlar L25/0.35). Single unbranched mesenteric venules (20–40 µm in diameter) were selected for study. A video camera mounted on the microscope projected the image onto a monitor, and the images were recorded for playback analysis, using a videocassette recorder. A video time/date generator projected the time, date, and stopwatch function onto the monitor. Images of the mesenteric microcirculation were recorded for 5 min, after a 15-min equilibration period. The end of this 5-min interval was considered as time zero. The mesentery was subsequently superfused for 1 min, with bicarbonate-buffered saline containing 10 µM of the different PAR2-APs (Tc-NH2, SL-NH2) or the control inactive peptides (LRGILS-NH2, LR-NH2 and LSIGRL-NH2, LS-NH2) and then superfused again with bicarbonate-buffered saline alone for the remainder of the experiment. The images were recorded for 5-min interval beginning at 15, 30, 45, and 60 min after the superfusion with PAR2-APs or the control peptides. Venular diameter was measured on-line using a video caliper (model 908; IPM, San Diego, CA). Leukocyte adherence was determined upon video playback. A leukocyte was considered adherent to the endothelium if it remained stationary for 30 s or more. Leukocyte flux was defined as the number of leukocytes per minute moving at a velocity less than that of the erythrocytes, which passed a reference point in the venule. The changes in flux of rolling leukocytes were evaluated as differences between the number of rolling leukocytes at each interval and the basal number of rolling leukocytes.
For the evaluation of the effects of drugs on leukocyte flux and adhesion, selected groups of rats were pretreated with compound 48/80, sodium cromoglycate, or WEB 2086. Compound 48/80 was used to deplete mast cells, as described before (22). Briefly, compound 48/80 (0.1% solution in 0.9% sterile saline) was injected i.p. to a group of rats (n = 6) each morning and evening for 4 days before the intravital microscopy experiment. The doses employed were 0.6 mg/kg for the first six injections and 1.2 mg/kg for the last two injections. The intravital microscopy experiments were performed 5–6 h after the final injection of compound 48/80. The control group (n = 5) for 48/80 experiments was treated for 4 days with saline, the vehicle for 48/80. A group of rats (n = 5) was treated with sodium cromoglycate, a mast cell stabilizer, i.v. (20 mg/kg), 1 h before the beginning of the experiment, and 0.33 mg/ml of sodium cromoglycate was added to the intravital perfusion buffer, as previously described (23). The control group (n = 5) received an i.v. injection of saline, the vehicle for sodium cromoglycate, and saline was also added to the perfusion buffer of this group. Other groups of rats were treated orally with WEB 2086 (10 mg/kg), 15 min before the beginning of the perfusion with SL-NH2 (n = 5) or Tc-NH2 (n = 6). WEB 2086 is a PAF receptor antagonist. This dose has been shown to be effective in preventing PAF-induced leukocyte rolling and adhesion in previous studies (23, 24). The control groups were treated with saline + 3% DMSO, the vehicle for WEB 2086.
Leukocyte extravasation
Three groups of rats received a 1-ml i.p. injection of, respectively, the PAR2-AP SL-NH2 (1 mg), the control peptide LR-NH2 (1 mg), or PBS, the vehicle for both peptides. Twenty-four hours later, the peritoneal cavities were washed with 10 ml of PBS + EDTA (3 mM) + heparin (50 U/ml), and lavage fluids were carefully collected. The lavage fluids were centrifuged for 5 min at 1200 rpm and the pellets were resuspended in 5 ml of PBS + EDTA (3 mM). Leukocyte migration was quantified by staining of lavage fluids with Turk’s solution and by counting extravasated cells using a Neubauer hematocytometer. Two other groups of rats were treated orally 15 min before the i.p. injection of the PAR2-AP SL-NH2 (1 mg in 1 ml of PBS), with either WEB 2086 (10 mg/kg) or the vehicle for WEB 2086. Eight hours after the i.p. injection of SL-NH2, these rats received another oral dose of either WEB 2086 (10 mg/kg) or vehicle. Leukocyte migration was quantitated in these two groups, 24 h after SL-NH2 injection, as described above.
Materials and Methods
All peptides, prepared by solid-phase synthesis, were obtained from the Peptide Synthesis Facility of the University of Calgary Faculty of Medicine (Dr. D. McMaster, director). The composition and purity of all peptides were confirmed by HPLC analysis, mass spectral analysis, and amino acid analysis. Stock solutions prepared in 25 mM HEPES buffer (pH 7.4) were analyzed by quantitative amino acid analysis to verify peptide concentration and purity. Compound 48/80 and sodium cromoglycate were obtained from Sigma (St. Louis, MO). WEB 2086 was provided by Boehringer Ingleheim (Ingleheim, Germany).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Superfusion of rat mesenteric venules for 1 min with 10 µM of a
specific PAR2-AP (SL-NH2)
significantly increased the flux of rolling leukocytes, from 15
to 60 min after the peptide addition. The control peptide
(LR-NH2) had no effect on leukocyte rolling (Fig. 1
).
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). From 15 min to 1 h after the
1-min perfusion of 10 µM of the two PAR2-APs
(SL-NH2 or Tc-NH2), the
number of adherent leukocytes significantly increased by about 3-fold
above basal levels (Fig. 2).
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).
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).
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To investigate the role of mast cells in the
PAR2-AP-induced increase in leukocyte adherence,
one group of rats was treated with compound 48/80, a mast cell
degranulator, and another group of rats was treated with sodium
cromoglycate, a mast cell stabilizer. The control groups were treated
with the respective vehicles. In the vehicle-treated groups, a
significant increase in leukocyte adhesion after perfusion with the
specific PAR2-AP Tc-NH2 was
observed at all time points (Fig. 4). In
48/80-treated rats, no inhibition of the
PAR2-AP-induced increase in leukocyte adhesion
was observed (Fig. 4). No difference in leukocyte adherence was
observed between the vehicle- and the sodium cromoglycate-treated group
of animals (Fig. 4).
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To determine whether PAF release was involved in the effects of
PAR2-activating peptide on leukocyte behavior,
rats were pretreated with either a PAF antagonist (WEB 2086) or
vehicle. In rats treated with WEB 2086, the increase in flux of rolling
leukocytes provoked by the addition of a specific
PAR2-AP (SL-NH2) was
completely inhibited (Fig. 1
). Similarly, the increase in leukocyte
adherence induced by the PAR2-APs
SL-NH2 and Tc-NH2 was
significantly reduced by WEB 2086. No difference in leukocyte adherence
was observed in WEB 2086-treated rats between the basal measurement and
each time point after the addition of PAR2-APs
(Fig. 5). These results showed that the
WEB 2086 treatment completely abolished the effect of selective
PAR2-APs on leukocyte adhesion. In rats treated
with the PAF antagonist WEB 2086, the increase in leukocyte
extravasation into the peritoneal cavity induced by
SL-NH2 was significantly reduced compared with
vehicle-treated rats. No difference in leukocyte recruitment was
observed between the WEB 2086-treated rats that had received an i.p.
injection of SL-NH2 and the rats that have
received either the inactive peptide (LR-NH2) or
buffer alone (Fig. 3). This final result showed that the WEB 2086
treatment completely inhibited the
PAR2-AP-induced increase in PMN recruitment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The events that regulate leukocyte migration toward inflammatory sites have been extensively investigated in recent years (26). In the initial phase, the rolling of leukocytes on the endothelium is a prerequisite for subsequent adhesion (27, 28) and is mainly mediated by the selectins (28, 29, 30). In this study, the activation of PAR2 by the selective PAR2-AP, SL-NH2, resulted in a significant increase in leukocyte rolling. Treatment of rats with the PAF antagonist WEB 2086 prevented the PAR2-AP-induced increase in flux of rolling leukocyte. This result is consistent with recent observations showing that PAF can induce leukocytes to roll on endothelium in vivo (31). The magnitude of the increase in leukocyte rolling observed in our study was comparable with the effect observed after the addition of PAF to the superfusion buffer (31).
The second step in the process of leukocyte emigration is firm adhesion of leukocytes to the venular endothelium, a mechanism dependent of the expression of the ß2 integrin on leukocyte membranes and their counterparts on the endothelium (32, 33, 34). The topical addition of either of two PAR2-APs elicited a profound increase in leukocyte adhesion. The magnitude of the increase in tight adhesion of leukocytes to the endothelium observed after the addition of PAR2-APs was comparable with the effects observed with known proinflammatory compounds such as the chemotactic peptide FMLP (35). At 60 min after the addition of PAR2-APs, we observed an increase in leukocyte adhesion from 3.7 ± 0.2 to 10.33 ± 1.26 for SL-NH2 and from 2.8 ± 0.3 to 10.2 ± 1 for Tc-NH2, compared with an increase of leukocyte adhesion from 3.66 ± 0.21 to 13.33 ± 1.05 after perfusion with FMLP (35). Considering the fact that PAR2-APs were added for only 1 min to the superfusion buffer, they induced a strong and long-lasting effect on leukocyte adhesion compared with the effect observed with FMLP that was constantly superfused all along the experiment.
Mast cells that are closely apposed to mesenteric venules are important cellular mediators of inflammation, inducing leukocyte infiltration (36, 37) and adhesion (23, 38). Befus et al. (39) have shown that PAR2 is expressed on rat mast cells and that the selective PAR2-APs Tc-NH2 and SL-NH2 are able to induce mast cell degranulation. We have investigated the possibility that PAR2 activation might cause mast cell degranulation, which could contribute to leukocyte adherence through the release of numerous mediators (histamine, leukotriene C4, PAF, leukotriene B4) that have been shown to induce leukocyte rolling and adhesion (24, 40, 41, 42, 43). The effects of Tc-NH2 were studied rather than SL-NH2 because in their experiments, Befus et al. have observed that Tc-NH2 was more potent than SL-NH2 to activate mast cells (39). Pretreatment with a mast cell stabilizer (sodium cromoglycate) did not significantly affect the extent of leukocyte adherence induced by a PAR2-AP. In rats chronically treated with compound 48/80, to degranulate mast cells, no inhibition of the Tc-NH2-induced effect on leukocyte adhesion was observed. These results strongly suggest that the PAR2-AP-induced increase in leukocyte adhesion is not mediated by mast cell degranulation.
It has been proposed that endothelial membrane-bound PAF is an important stimulus for leukocyte adhesion (42, 44, 45). We have investigated the possibility that the PAR2-AP-induced increase in leukocyte adherence could be mediated by PAF. Remarkably, the proadherent effect of the two selective PAR2-APs was completely inhibited in rats treated with a PAF antagonist (WEB 2086). The magnitude of the effect on leukocyte adherence that we observed after the addition of PAR2-APs was comparable with the effect observed after the superfusion of rat mesenteric venule with 5 nM of PAF (45). On the basis of these data, it is likely that PAR2-AP-induced PAF release in turn activates leukocytes to adhere to the endothelium. Our studies of rats pretreated with compound 48/80 and sodium cromoglycate suggest that mast cells are not the source of PAF production in this model. Leukocytes, and in particular neutrophils, which express PAR2 (20), might be responsible for PAF production after being activated by PAR2-APs. Nevertheless, it is also possible that endothelial cells, which express PAR2 (10, 15, 46), may also release PAF. It has been postulated that during P-selectin-induced leukocyte rolling, PAF, which remains endothelial cell associated, can interact with a leukocyte receptor, thereby activating CD11/CD18 and inducing adhesion (47).
It is well known that PAF participates in inflammatory disorders,
inducing most of the cardinal features of inflammation (increased
permeability, changes in vascular tone, increased rolling, and
adherence of leukocytes) (31, 42, 44, 45, 48, 49). It has
been shown that low concentrations of PAF induced a slight
vasodilatation, and higher concentrations caused vasoconstriction
(48, 49). In our study, if PAR2-APs
were able to induce PAF release, thus causing an increase in leukocyte
rolling and adhesion, PAF release should also have induced changes in
vessel diameter. However, all along the intravital microscopy
experiments, no change in vessel diameter was observed after the
addition of PAR2-APs (Table I). It appears that
the effects of PAF are very different according to the tissues and to
the animal species. In contrast to other vascular beds, in rat
mesenteric venules of 20–40 µm in diameter, it has been shown that
different concentrations of PAF (from 0.1–100 nM) had no effect on
vessel diameter (45). These results parallel our results,
confirming a possible induction of PAF release after
PAR2 activation that can induce leukocyte rolling
and adhesion without affecting venule diameter.
The results discussed in the above paragraphs showed that PAR2-APs were able to induce leukocyte rolling and adhesion to the endothelium. The next step in leukocyte recruitment is extravasation; therefore, we also wanted to determine whether leukocyte extravasation resulted from the rolling and adhesion can also be induced by PAR2-APs. Following injection of a specific PAR2-AP i.p., we observed a significant increase in leukocyte extravasation into the peritoneal cavity. The amount of polymorphonuclear cells recovered in the peritoneal lavage 24 h after the injection of PAR2-APs was lower than the amount of cells counted after LPS treatment at the same time point (50), suggesting that PAR2-AP is less potent than LPS for inducing leukocyte extravasation. The effects of the PAR2-AP were observed only 24 h after the peptide injection; the maximal effect of PAR2-AP might occur at a different time point. Nonetheless, a 4-fold increase in the number of extravasated leukocytes was observed after PAR2-AP injection compared with the number of cells collected after the injection of the control peptide. These results indicate that PAR2-APs not only act on leukocyte rolling and adherence, but are also able to induce leukocyte extravasation, allowing the leukocytes to migrate to the inflammatory site. We also observed transmigration of leukocytes through the venule wall at the end of several intravital microscopy experiments (60 min and later after the addition of PAR2-APs). This effect was never observed after the addition of the control peptide (data not shown). As was the case with leukocyte rolling and adherence, this leukocyte recruitment into the peritoneal cavity was completely inhibited by a PAF antagonist. This result was entirely consistent with previous studies that have shown that PAF can induce leukocyte extravasation (51, 52). Taken together, these results suggest that in rat, PAF is one of the principal mediators of the PAR2-AP-induced leukocyte recruitment.
PAR2 can be activated by trypsin in certain tissues in which trypsin is present, such as the intestine. In fact, it has been shown that trypsin and PAR2-APs can stimulate the production of eicosanoids by enterocytes and by everted sacs of jejunum (53). However, other tissues that express PAR2 are unlikely to be exposed to trypsin. Other proteinases might therefore be responsible for PAR2 activation in vivo, particularly in cases of inflammatory reactions. Mast cells are involved in many inflammatory reactions as effector cells that initiate the inflammatory response by releasing a variety of proinflammatory mediators. Among the mediators released during mast cell degranulation, proteinases represent the major protein constituent. Tryptase, which is one of the proteinases released by human mast cells, is able to cleave and activate PAR2 (7, 8). Thus, tryptase or other mast cell proteinases represent good candidates for the activation of PAR2 in vivo, during inflammatory processes. Another possibility is that PAR2 might be activated in vivo by the proteinases produced by pathogenic organisms such as bacteria. Proteinases released by bacteria are believed to play a critical role in the virulence of the organism, and thus in the initiation and progression of the inflammatory reaction caused by this pathogen agent. It has been shown that Gingipain-R, the major proteinase from Porphyromonas gingivalis, a causative agent of adult periodontal disease, was able to activate PAR2 on neutrophil (54). Moreover, Gingipain-R has been shown to enhance vascular permeability (55) and to activate the complement system (56), thus contributing to the initiation of the inflammatory reaction. We have shown that PAR2 activation leads to an increase in leukocyte rolling, adhesion, and extravasation, and we know that PAR2 activation also causes changes in vascular tone and permeability (10, 13, 14, 15, 16, 25). If PAR2 is activated by bacterial proteinases, this receptor might constitute one of the first alarm mechanisms that can signal the invasion of bacterial pathogens, so as to activate a primary inflammatory response.
In conclusion, this study demonstrates that PAR2-APs can indeed initiate leukocyte rolling, adhesion, and extravasation. These effects of PAR2-APs on leukocyte adherence and recruitment were independent of mast cell activation, but were mediated by the release of PAF. These results therefore suggest novel functions for proteinases during the inflammatory reaction. Proteinases are traditionally viewed as degradative enzymes, but by activating PARs and particularly PAR2, they might also act as signaling molecules that actively participate in the inflammatory process.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nathalie Vergnolle, Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N4N1 Canada. E-mail address:
3 Abbreviations used in this paper: PAR, proteinase-activated receptor; PAF, platelet-activating factor; PAR-AP, PAR-activating peptide; Tc-NH2, trans-cinnamoyl-LIGRLO-NH2; LR-NH2, LRGILS-NH2; LSIGRL-NH2, LS-NH2; SLIGRL-NH2, SL-NH2.
Received for publication June 14, 1999. Accepted for publication August 19, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-thrombin receptor coupled to Ca2+ mobilization. FEBS Lett. 288:123.[Medline]
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 K. Cederqvist, C. Haglund, P. Heikkila, T. Sorsa, T. Tervahartiala, U.-H. Stenman, and S. Andersson Pulmonary Trypsin-2 in the Development of Bronchopulmonary Dysplasia in Preterm Infants Pediatrics, September 1, 2003; 112(3): 570 - 577. [Abstract] [Full Text] [PDF]
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S. J. Bolton, C. A. McNulty, R. J. Thomas, C. R. A. Hewitt, and A. J. Wardlaw Expression of and functional responses to protease-activated receptors on human eosinophils J. Leukoc. Biol., July 1, 2003; 74(1): 60 - 68. [Abstract] [Full Text] [PDF]
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 C. D. Major, R. J. Santulli, C. K. Derian, and P. Andrade-Gordon Extracellular Mediators in Atherosclerosis and Thrombosis: Lessons From Thrombin Receptor Knockout Mice Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 931 - 939. [Abstract] [Full Text] [PDF]
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R. C. Fields, J. G. Schoenecker, J. P. Hart, M. R. Hoffman, S. V. Pizzo, and J. H. Lawson Protease-Activated Receptor-2 Signaling Triggers Dendritic Cell Development Am. J. Pathol., June 1, 2003; 162(6): 1817 - 1822. [Abstract] [Full Text] [PDF]
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S. Dulon, C. Cande, N. W. Bunnett, M. D. Hollenberg, M. Chignard, and D. Pidard Proteinase-Activated Receptor-2 and Human Lung Epithelial Cells: Disarming by Neutrophil Serine Proteinases Am. J. Respir. Cell Mol. Biol., March 1, 2003; 28(3): 339 - 346. [Abstract] [Full Text] [PDF]
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L. A. Boven, N. Vergnolle, S. D. Henry, C. Silva, Y. Imai, J. Holden, K. Warren, M. D. Hollenberg, and C. Power Up-Regulation of Proteinase-Activated Receptor 1 Expression in Astrocytes During HIV Encephalitis J. Immunol., March 1, 2003; 170(5): 2638 - 2646. [Abstract] [Full Text] [PDF]
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 R. Lang, P. I. Song, F. J. Legat, R. M. Lavker, B. Harten, H. Kalden, E. F. Grady, N. W. Bunnett, C. A. Armstrong, and J. C. Ansel Human Corneal Epithelial Cells Express Functional PAR-1 and PAR-2 Invest. Ophthalmol. Vis. Sci., January 1, 2003; 44(1): 99 - 105. [Abstract] [Full Text] [PDF]
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 R. C. Landis Aprotinin: Antithrombotic and Vasoactive Mechanisms of Action Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2002; 6(4): 307 - 312. [Abstract] [PDF]
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F. Schmidlin, S. Amadesi, K. Dabbagh, D. E. Lewis, P. Knott, N. W. Bunnett, P. R. Gater, P. Geppetti, C. Bertrand, and M. E. Stevens Protease-Activated Receptor 2 Mediates Eosinophil Infiltration and Hyperreactivity in Allergic Inflammation of the Airway J. Immunol., November 1, 2002; 169(9): 5315 - 5321. [Abstract] [Full Text] [PDF]
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N. Cenac, A.-M. Coelho, C. Nguyen, S. Compton, P. Andrade-Gordon, W. K. MacNaughton, J. L. Wallace, M. D. Hollenberg, N. W. Bunnett, R. Garcia-Villar, et al. Induction of Intestinal Inflammation in Mouse by Activation of Proteinase-Activated Receptor-2 Am. J. Pathol., November 1, 2002; 161(5): 1903 - 1915. [Abstract] [Full Text] [PDF]
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 A. F. Milia, M. B. Salis, T. Stacca, A. Pinna, P. Madeddu, M. Trevisani, P. Geppetti, and C. Emanueli Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia Circ. Res., August 23, 2002; 91(4): 346 - 352. [Abstract] [Full Text] [PDF]
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 Y. Wang, Y. Gu, and M. J. Lucas Expression of Thrombin Receptors in Endothelial Cells and Neutrophils from Normal and Preeclamptic Pregnancies J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3728 - 3734. [Abstract] [Full Text] [PDF]
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 G. R. Stenton, O. Nohara, R. E. Dery, H. Vliagoftis, M. Gilchrist, A. Johri, J. L. Wallace, M. D. Hollenberg, R. Moqbel, and A. D. Befus Proteinase-Activated Receptor (PAR)-1 and -2 Agonists Induce Mediator Release from Mast Cells by Pathways Distinct from PAR-1 and PAR-2 J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 466 - 474. [Abstract] [Full Text] [PDF]
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N. Vergnolle, C. K. Derian, M. R. D'Andrea, M. Steinhoff, and P. Andrade-Gordon Characterization of Thrombin-Induced Leukocyte Rolling and Adherence: A Potential Proinflammatory Role for Proteinase-Activated Receptor-4 J. Immunol., August 1, 2002; 169(3): 1467 - 1473. [Abstract] [Full Text] [PDF]
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A. Maree and D. Fitzgerald PAR2 Is Partout and Now in the Heart Circ. Res., March 8, 2002; 90(4): 366 - 368. [Full Text] [PDF]
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P. G. McLean, D. Aston, D. Sarkar, and A. Ahluwalia Protease-Activated Receptor-2 Activation Causes EDHF-Like Coronary Vasodilation: Selective Preservation in Ischemia/Reperfusion Injury: Involvement of Lipoxygenase Products, VR1 Receptors, and C-Fibers Circ. Res., March 8, 2002; 90(4): 465 - 472. [Abstract] [Full Text] [PDF]
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S. Fiorucci, A. Mencarelli, B. Palazzetti, E. Distrutti, N. Vergnolle, M. D. Hollenberg, J. L. Wallace, A. Morelli, and G. Cirino Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis PNAS, November 20, 2001; 98(24): 13936 - 13941. [Abstract] [Full Text] [PDF]
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A. Alvarez and M.-J. Sanz Reactive oxygen species mediate angiotensin II-induced leukocyte-endothelial cell interactions in vivo J. Leukoc. Biol., August 1, 2001; 70(2): 199 - 206. [Abstract] [Full Text] [PDF]
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 S. R. Macfarlane, M. J. Seatter, T. Kanke, G. D. Hunter, and R. Plevin Proteinase-Activated Receptors Pharmacol. Rev., June 1, 2001; 53(2): 245 - 282. [Abstract] [Full Text] [PDF]
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J. R. Lindner, M. L. Kahn, S. R. Coughlin, G. R. Sambrano, E. Schauble, D. Bernstein, D. Foy, A. Hafezi-Moghadam, and K. Ley Delayed Onset of Inflammation in Protease-Activated Receptor-2-Deficient Mice J. Immunol., December 1, 2000; 165(11): 6504 - 6510. [Abstract] [Full Text] [PDF]
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H. Tapper and H. Herwald Modulation of hemostatic mechanisms in bacterial infectious diseases Blood, October 1, 2000; 96(7): 2329 - 2337. [Full Text] [PDF]
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E. Camerer, W. Huang, and S. R. Coughlin Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa PNAS, May 9, 2000; 97(10): 5255 - 5260. [Abstract] [Full Text] [PDF]
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S. J. Compton, J. A. Cairns, K.-J. Palmer, B. Al-Ani, M. D. Hollenberg, and A. F. Walls A Polymorphic Protease-activated Receptor 2 (PAR2) Displaying Reduced Sensitivity to Trypsin and Differential Responses to PAR Agonists J. Biol. Chem., December 8, 2000; 275(50): 39207 - 39212. [Abstract] [Full Text] [PDF]
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 J. J. Ubl, Z. V. Grishina, T. K. Sukhomlin, T. Welte, F. Sedehizade, and G. Reiser Human bronchial epithelial cells express PAR-2 with different sensitivity to thermolysin Am J Physiol Lung Cell Mol Physiol, June 1, 2002; 282(6): L1339 - L1348. [Abstract] [Full Text] [PDF]
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P. G. McLean, D. Aston, D. Sarkar, and A. Ahluwalia Protease-Activated Receptor-2 Activation Causes EDHF-Like Coronary Vasodilation: Selective Preservation in Ischemia/Reperfusion Injury: Involvement of Lipoxygenase Products, VR1 Receptors, and C-Fibers Circ. Res., March 8, 2002; 90(4): 465 - 472. [Abstract] [Full Text] [PDF]
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J. R. Hamilton, A. G. Frauman, and T. M. Cocks Increased Expression of Protease-Activated Receptor-2 (PAR2) and PAR4 in Human Coronary Artery by Inflammatory Stimuli Unveils Endothelium-Dependent Relaxations to PAR2 and PAR4 Agonists Circ. Res., July 6, 2001; 89(1): 92 - 98. [Abstract] [Full Text] [PDF]
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