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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 394-398, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0250TR

Translational Review

Neutrophil and Pathogen Proteinases versus Proteinase-Activated Receptor-2 Lung Epithelial Cells

More Terminators than Activators

Michel Chignard and Dominique Pidard

Unité de Défense Innée et Inflammation, Institut Pasteur; Inserm, E336, Paris, France

Correspondence and requests for reprints should be addressed to Michel Chignard, Unité de Défense Innée et Inflammation/Inserm E336, Institut Pasteur, Paris, F-75015 France. E-mail: chignard{at}pasteur.fr


   Abstract
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 Abstract
Neutrophil and Bacterial...
 PAR-2 and Lungs
 Neutrophil and Bacterial...
 References
 
The proteinase-activated receptor-2 (PAR-2) is expressed by different lung cells, including bronchial and alveolar epithelial cells. Since its discovery in 1995, numerous in vivo and in vitro studies have demonstrated its involvement in lung inflammation, whether from infectious or allergic causes. However, its role is controversial because there is evidence of both pro- and anti-inflammatory activities. PARs, including PAR-2, display a unique activation process. Specific proteinases cleave the N-terminal extracellular domain at a particular site. The new N-terminal sequence functions as a tethered ligand and binds intramolecularly to activate the receptor. Recently, other specific proteinases have been shown to cleave the N-terminal exodomain at other sites, resulting in a disarming of the receptor. Some of these activating and disabling proteinases are produced by host cells and others by pathogens, and may be present in the airspaces under diverse pathophysiologic settings.


   Neutrophil and Bacterial Proteinases in the Lungs
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 Abstract
 Neutrophil and Bacterial...
PAR-2 and Lungs
 Neutrophil and Bacterial...
 References
 
Lungs are constantly exposed to a multitude of airborne microorganisms, and consequently the respiratory tract has to confront diverse harmful agents. There is an integrated mechanism of defense, part of the innate immune system, to maintain sterility of the distal airways and alveoli. If there is pathogen overload or a defect of the host defense, bacteria, viruses, and fungi can develop, causing pneumonia characterized by a massive inflammatory reaction. The inflammation is largely due to excessive influx of polymorphonuclear neutrophils (PMN) from the blood into airways and alveoli (1–3). PMN are summoned into the pulmonary spaces to control infection but excessive numbers can injure the host tissues, in particular through the release of serine proteinases (4, 5). Indeed, various acute and chronic inflammatory lung diseases including acute respiratory distress syndrome (ARDS), pneumonia, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), are associated with a high PMN load.

Neutrophil elastase (NE), cathepsin G (CG), and proteinase 3 (PR3) are serine proteinases stored in the azurophilic granules of PMN. They participate in the killing and digestion of phagocytozed microorganisms. However, when released from activated PMN into the airspaces, they can proteolyze extracellular matrix components and immune effector proteins, including membrane receptors, thereby damaging host tissues (6). This is particularly manifest in chronic inflammatory diseases including COPD (7) and CF (8). In CF, another proteinase (in addition to NE, CG, and PR3) is recovered from the sputum of patients: elastase from Pseudomonas aeruginosa, the most frequent pathogen in the lungs of patients with CF. It is an elastolytic metalloproteinase, also known as LasB or pseudolysin, and hereafter referred to as EPa, and which can damage tissues and components of the immune system (9, 10).

These proteinases can also activate cells. In particular, NE (11) and EPa (12) induce IL-8 secretion by lung epithelial cells. The mechanisms by which serine proteinases modulated cellular responses were largely unknown until the discovery of the first proteinase-activated receptor (PAR), the thrombin receptor PAR-1 (13, 14).


   PAR-2 and Lungs
Top
 Abstract
 Neutrophil and Bacterial...
 PAR-2 and Lungs
Neutrophil and Bacterial...
 References
 
PARs comprise a unique family of G protein–coupled, seven transmembrane-domain receptors, cleaved at an activation site within the N-terminal exodomain by a variety of serine proteinases. Following the cleavage, the new N-terminal sequence functions as a tethered ligand that binds intramolecularly to activate the receptor (15, 16). In addition to PAR-1 (13, 14), three other receptors have been identified: PAR-2 (17, 18), PAR-3 (19), and PAR-4 (20). PAR-1 and PAR-3 are both preferentially cleaved by thrombin, PAR-2 by trypsin and tryptase, and PAR-4 is activated by thrombin, trypsin, plasmin, and CG. All PARs, except PAR-3, can be selectively activated by short synthetic peptides corresponding to their tethered ligand (15, 16). Thus, trypsin cleaves the N-terminal exodomain of human PAR-2 at SKGR36{downarrow}37SLIGKV (where {downarrow} designates the cleavage site), unmasking the N-terminal tethered ligand SLIGKV..., whereas the synthetic peptide SLIGKV–NH2 activates PAR-2 without the need for receptor cleavage (15, 16).

Activation of PAR-2 is generally considered as proinflammatory (see Ref. 21 for a review) on the basis of experimental data including various in vivo models of inflammation with PAR-2–deficient mice (Table 1). The picture is nonetheless not so clear in the lung as PAR-2 activation may have either proinflammatory or protective effects. The protective activity was first described using murine models: intranasal administration of the synthetic activating peptide does not trigger an inflammatory response but inhibits lipopolysaccharide (LPS)-induced PMN recruitment in the airways (29). Other experiments (30) identified PAR-2–dependent cytoprotection linked to the induction of prostaglandin E2 (PGE2) production. Nonetheless, respiratory epithelial cells in vitro, whether primary cells or cell lines, can be activated through PAR-2 to release not only PGE2 but also proinflammatory effectors including matrix metalloproteinase-9 (MMP-9) (31), granulocyte macrophage-colony stimulating factor (GM-CSF) (32, 33), eotaxin (33), IL-6, and IL-8 (34). Thus, PAR-2 may participate in some aspects of lung inflammation.


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  		TABLE 1. EVIDENCE FOR IMPLICATION OF PAR-2 IN INFLAMMATION BASED ON STUDIES USING PAR-2–DEFICIENT MICE

 
There is similarly contradictory evidence about the role of PAR-2 in allergic respiratory diseases: PAR-2 may contribute to asthma (Table 2); however, two recent reports based on murine models of allergic inflammation and treatments with the murine synthetic activating peptide SLIGRL–NH2, reached opposite conclusions. For Ebeling and colleagues (38), PAR-2 activation enhances antigen-mediated airways inflammation and airway hyperresponsiveness, whereas De Campo and Henry (39) report that PAR-2 activation inhibits airway eosinophilia and hyperresponsiveness. Although the experimental approaches were similar, the concentrations of the activating peptide used were different (around 60 µg/kg for Ebeling and coworkers and of 25 mg/kg for De Campo and Henry). Schmidlin and coworkers (23) were the first to report that PAR-2 mediates eosinophil infiltration and hyperactivity in allergic inflammation of the airways in mice, and used a low concentration (165 µg/kg) of SLIGRL–NH2. De Campo and Henry (39) link their observed inhibitory effect to the synthesis of PGE2, a lipid mediator with bronchoprotective and anti-inflammatory activities in the lungs (40). Possibly, PGE2 is only produced or produced at effective concentrations when PAR-2 is activated strongly. High concentrations of the activating peptide may either maintain its presence in the cell environment and thus cause sustained activation of the cells, or allow greater diffusion so that more cell receptors or several cell populations are affected. Of note is the fact that in the murine model of LPS-induced lung inflammation, the recruitment of PMN into the airways is inhibited by 20 mg/kg SLIGRL–NH2 (29). The discrepancies between the pro- and anti-inflammatory properties described for this receptor in the lung may result from PAR-2 activation triggering, or not triggering, the synthesis of effective quantities of PGE2. In support of this, during viral infection, the upregulation of PAR-2 in the airways is coupled to an increased activation of cyclooxygenase with possibly enhanced generation of PGE2, conferring protection against experimental metacholine-induced bronchoconstriction (41). Possibly there is robust or sustained activation of PAR-2 during chronic inflammation (COPD, CF), in which case PAR-2 would be anti-inflammatory. In contrast, acute lung inflammation (ARDS, pneumonia) may be associated with weak or brief activation with proinflammatory effects.


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  		TABLE 2. EXPERIMENTAL AND CLINICAL EVIDENCE FOR A CONTRIBUTION OF PAR-2 TO ALLERGIC INFLAMMATION OF THE AIRWAYS

 
In addition to understanding its role in infectious and allergic lung inflammation, another issue is the activation of PAR-2 in the lung environment, that is, the identity of the activating proteinase(s). PAR-2 is expressed by various cell types in the lung including endothelial cells, smooth muscle cells, fibroblasts (37, 42–44), resident alveolar macrophages (45), and recruited PMN (46). Respiratory epithelial cells obviously also express PAR-2, and mostly on their apical side (47). PAR-2 is thus directly exposed to proteases present in the airspaces, but the involvement of the locally expressed trypsin-like proteinases in PAR-2 activation remains to be established. There are several candidates (as indicated in Table 3), of which tryptase is the most likely. However, tryptase is released by mast cells, which are localized in the parenchyma. Thus, it is unclear how this proteinase, which is large and diffuses poorly, encounters PAR-2 on the apical surface of epithelial cells. No role for tryptase in vivo has ever been demonstrated, as is also the case for the other proteinases listed.


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  		TABLE 3. POTENTIAL AGONISTS OF PAR-2 EXPRESSED BY RESPIRATORY EPITHELIAL CELLS

 
As mentioned above, during the infection/inflammation process, PMN and their proteinases and proteinases released by pathogens are present in the airspaces. Testing the activity of such proteinases on PAR-2 was an obvious idea. Thus, NE and CG have been tested as has elastase from Pseudomonas aeruginosa (EPa).


   Neutrophil and Bacterial Proteinases versus PAR-2
Top
 Abstract
 Neutrophil and Bacterial...
 PAR-2 and Lungs
 Neutrophil and Bacterial...
References
 
Bronchial (16-HBE) and alveolar (A549) human epithelial cell lines and a constitutive human PAR-2–expressing cell line (KNRK/PAR-2) have been studied. None of the proteinases tested (NE, CG, and EPa) activated any of these three cell lines as assessed by following cytosolic calcium movements. However, when cells were briefly exposed to these proteinases, they became unresponsive to subsequent exposure to trypsin, the archetypal PAR-2 agonist. PAR-2 was, however, still present at the cell surface, as revealed by the response to the synthetic activating peptide, SLIGKV–NH2. The use of specific antibodies revealed that part of the N-terminal exodomain of PAR-2 was missing after treatment with either NE, CG, or EPa (51, 52). Similar data have been reported for thermolysin, the prototype of the M4 family of metalloproteinases, which includes several proteases produced by bacteria involved in lung pathology (53).

The hypothesis was that PAR-2 is disabled by a cleavage in its N-terminal exodomain somewhere between the cleavage/activation site (Arg36-Ser37) and the first transmembrane domain. This was reminiscent of previous findings for PAR-1 (54) showing specific inhibition by NE, CG, and PR3 of thrombin-induced platelet or endothelial cell activation. Distinct cleavage sites were evidenced within the N-terminal exodomain of PAR-1, downstream from the thrombin cleavage site (54).

The disarming cleavage sites on PAR-2 were determined by mass spectrometry–based analysis of the proteinase-induced fragmentation by NE and CG of a recombinant N-terminal domain (Arg31 to Pro79) (55) and of EPa cleavage of three overlapping synthetic peptides corresponding to the portion of PAR-2 from Lys34 to Pro79 (52). Several potential cleavage sites were identified, namely one for NE at Val76, two for CG at Phe59 and Phe64, and two for EPa at Ser37 and Gly52 (Figure 1).


Figure 1
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  		Figure 1. Schematic representation of the N-terminal exodomain of PAR-2 expressed by epithelial cells and showing the potential cleavage sites of NE, CG, PR3, and EPa. Activating and disabling proteinases are indicated in blue and pink, respectively. The amino acid sequence depicted in red corresponds to the tethered activating sequence unmasked upon the activation cleavage of PAR-2 at Arg36-Ser37. NE, neutrophil elastase; CG, cathepsin G; PR3, proteinase 3; EPa, elastase from P. aeruginosa.

 
Confusingly, NE and CG have both been shown not to disarm but to activate PAR-2 expressed by nonepithelial cells (56). A possible explanation is that the pattern of gycosylation of PAR-2 depends on the producing cell type. Indeed, the susceptibility of PAR-2 to cleavage/activation by tryptase can be altered by the glycosylation pattern of its N-terminal exodomain (57, 58). There is another unresolved discrepancy for PR3, the third serine proteinase released by activated PMN: both activation of PAR-2 in oral epithelial cells through cleavage at Arg36-Ser37 (59) and potentially disarming cleavage sites downstream from Ser37 (55) have been reported (Figure 1).

Conclusions
PAR-2 expressed by respiratory epithelial cells is susceptible to cleavage by various proteinases of diverse classes and from different sources. These proteinases can display opposite effects, either activating or disabling PAR-2 (see Table 4). The "terminator" activity of proteases such as those released by PMN or by P. aeruginosa may have important biological consequences. Indeed, although the precise pathophysiologic role for PAR-2 in the lung has yet to be established with certainty, the currently available evidence suggests that this proteolytically activated receptor is an important component of the innate defense of the lung (60, 61). If true, PAR-2 contributes to the fight against invading microbes like P. aeruginosa, as well as to the process of tissue protection and repair. Consequently, its crippling by EPa, and possibly by a combination of EPa and PMN proteinases in an infectious/inflammatory context, could promote the success of pathogenic microorganisms in colonizing the lung, and impede the respiratory defense and repair mechanisms, thus contributing to the progression of the disease.


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  		TABLE 4. DIFFERENTIAL EFFECTS OF PROTEINASES LIKELY TO BE PRESENT IN THE AIRSPACES ON PAR-2 EXPRESSED BY RESPIRATORY EPITHELIAL CELLS

 

   Footnotes
 
DOI: 10.1165/rcmb.2005-0250TR

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form July 8, 2005

Accepted in final form November 23, 2005


   References
Top
 Abstract
 Neutrophil and Bacterial...
 PAR-2 and Lungs
 Neutrophil and Bacterial...
 References
 

  1. Boyton RJ, Openshaw PJ. Pulmonary defences to acute respiratory infection. Br Med Bull 2002;61:1–12.[Abstract/Free Full Text]
  2. Hiemstra PS, Bals R. Series introduction: Innate host defense of the respiratory epithelium. J Leukoc Biol 2004;75:3–4.[Abstract/Free Full Text]
  3. Bals R, Hiemstra PS. Innate immunity in the lung: how epithelial cells fight against respiratory pathogens. Eur Respir J 2004;23:327–333.[Abstract/Free Full Text]
  4. Gando S, Kameue T, Matsuda N, Sawamura A, Hayakawa M, Kato H. Systemic inflammation and disseminated intravascular coagulation in early stage of ALI and ARDS: role of neutrophil and endothelial activation. Inflammation 2004;28:237–244.[CrossRef][Medline]
  5. Mendez JL, Hubmayr RD. New insights into the pathology of acute respiratory failure. Curr Opin Crit Care 2005;11:29–36.[Medline]
  6. Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, Halbwachs-Mecarelli L. Neutrophils: molecules, functions and pathophysiological aspects. Lab Invest 2000;80:617–653.[Medline]
  7. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 2003;22:672–688.[Abstract/Free Full Text]
  8. Donaldson SH, Boucher RC. Update on pathogenesis of cystic fibrosis lung disease. Curr Opin Pulm Med 2003;9:486–491.[CrossRef][Medline]
  9. Doring G, Obernesser HJ, Botzenhart K, Flehmig B, Hoiby N, Hofmann A. Proteases of Pseudomonas aeruginosa in patients with cystic fibrosis. J Infect Dis 1983;147:744–750.[Medline]
  10. Buret A, Cripps AW. The immunoevasive activities of Pseudomonas aeruginosa: relevance for cystic fibrosis. Am Rev Respir Dis 1993;148:793–805.[Medline]
  11. Nakamura H, Yoshimura K, McElvaney NG, Crystal RG. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J Clin Invest 1992;89:1478–1484.[Medline]
  12. Azghani AO, Baker JW, Shetty S, Miller EJ, Bhat GJ. Pseudomonas aeruginosa elastase stimulates ERK signaling pathway and enhances IL-8 production by alveolar epithelial cells in culture. Inflamm Res 2002;51:506–510.[CrossRef][Medline]
  13. Vu TK, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991;64:1057–1068.[CrossRef][Medline]
  14. Rasmussen UB, Vouret-Craviari V, Jallat S, Schlesinger Y, Pages G, Pavirani A, Lecocq JP, Pouyssegur J, Van Obberghen-Schilling E. cDNA cloning and expression of a hamster alpha-thrombin receptor coupled to Ca2+ mobilization. FEBS Lett 1991;288:123–128.[CrossRef][Medline]
  15. Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R. Proteinase-activated receptors. Pharmacol Rev 2001;53:245–282.[Abstract/Free Full Text]
  16. Hollenberg MD, Compton SJ. International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol Rev 2002;54:203–217.[Abstract/Free Full Text]
  17. Nystedt S, Emilsson K, Larsson AK, Strombeck B, Sundelin J. Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2. Eur J Biochem 1995;232:84–89.[Medline]
  18. Bohm SK, Kong W, Bromme D, Smeekens SP, Anderson DC, Connolly A, Kahn M, Nelken NA, Coughlin SR, Payan DG, et al. Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J 1996;314:1009–1016.[Medline]
  19. Ishihara H, Connolly AJ, Zeng D, Kahn ML, Zheng YW, Timmons C, Tram T, Coughlin SR. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 1997;386:502–506.[CrossRef][Medline]
  20. Xu WF, Andersen H, Whitmore TE, Presnell SR, Yee DP, Ching A, Gilbert T, Davie EW, Foster DC. Cloning and characterization of human protease-activated receptor 4. Proc Natl Acad Sci USA 1998;95:6642–6646.[Abstract/Free Full Text]
  21. Ossovskaya VS, Bunnett NW. Protease-activated receptors: contribution to physiology and disease. Physiol Rev 2004;84:579–621.[Abstract/Free Full Text]
  22. Lindner JR, Kahn ML, Coughlin SR, Sambrano GR, Schauble E, Bernstein D, Foy D, Hafezi-Moghadam A, Ley K. Delayed onset of inflammation in protease-activated receptor-2-deficient mice. J Immunol 2000;165:6504–6510.[Abstract/Free Full Text]
  23. Schmidlin F, Amadesi S, Dabbagh K, Lewis DE, Knott P, Bunnett NW, Gater PR, Geppetti P, Bertrand C, Stevens ME. Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J Immunol 2002;169:5315–5321.[Abstract/Free Full Text]
  24. Cenac N, Coelho AM, Nguyen C, Compton S, Andrade-Gordon P, MacNaughton WK, Wallace JL, Hollenberg MD, Bunnett NW, Garcia-Villar R, et al. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am J Pathol 2002;161:1903–1915.[Abstract/Free Full Text]
  25. Kawagoe J, Takizawa T, Matsumoto J, Tamiya M, Meek SE, Smith AJ, Hunter GD, Plevin R, Saito N, Kanke T, et al. Effect of protease-activated receptor-2 deficiency on allergic dermatitis in the mouse ear. Jpn J Pharmacol 2002;88:77–84.[CrossRef][Medline]
  26. Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R, Meek SE, Smith AJ, Hunter GD, McLean JS, McGarry F, et al. Essential role for proteinase-activated receptor-2 in arthritis. J Clin Invest 2003;111:35–41.[CrossRef][Medline]
  27. Seeliger S, Derian CK, Vergnolle N, Bunnett NW, Nawroth R, Schmelz M, Von Der Weid PY, Buddenkotte J, Sunderkotter C, Metze D, et al. Proinflammatory role of proteinase-activated receptor-2 in humans and mice during cutaneous inflammation in vivo. FASEB J 2003;17:1871–1885.[Abstract/Free Full Text]
  28. Hansen KK, Sherman PM, Cellars L, Andrade-Gordon P, Pan Z, Baruch A, Wallace JL, Hollenberg MD, Vergnolle N. A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis. Proc Natl Acad Sci USA 2005;102:8363–8368.[Abstract/Free Full Text]
  29. Moffatt JD, Jeffrey KL, Cocks TM. Protease-activated receptor-2 activating peptide SLIGRL inhibits bacterial lipopolysaccharide-induced recruitment of polymorphonuclear leukocytes into the airways of mice. Am J Respir Cell Mol Biol 2002;26:680–684.[Abstract/Free Full Text]
  30. Cocks TM, Fong B, Chow JM, Anderson GP, Frauman AG, Goldie RG, Henry PJ, Carr MJ, Hamilton JR, Moffatt JD. A protective role for protease-activated receptors in the airways. Nature 1999;398:156–160.[CrossRef][Medline]
  31. Vliagoftis H, Schwingshackl A, Milne CD, Duszyk M, Hollenberg MD, Wallace JL, Befus AD, Moqbel R. Proteinase-activated receptor-2-mediated matrix metalloproteinase-9 release from airway epithelial cells. J Allergy Clin Immunol 2000;106:537–545.[CrossRef][Medline]
  32. Sun G, Stacey MA, Schmidt M, Mori L, Mattoli S. Interaction of mite allergens Der p3 and Der p9 with protease-activated receptor-2 expressed by lung epithelial cells. J Immunol 2001;167:1014–1021.[Abstract/Free Full Text]
  33. Vliagoftis H, Befus AD, Hollenberg MD, Moqbel R. Airway epithelial cells release eosinophil survival-promoting factors (GM-CSF) after stimulation of proteinase-activated receptor 2. J Allergy Clin Immunol 2001;107:679–685.[CrossRef][Medline]
  34. Asokananthan N, Graham PT, Fink J, Knight DA, Bakker AJ, McWilliam AS, Thompson PJ, Stewart GA. Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells. J Immunol 2002;168:3577–3585.[Abstract/Free Full Text]
  35. Molino M, Barnathan ES, Numerof R, Clark J, Dreyer M, Cumashi A, Hoxie JA, Schechter N, Woolkalis M, Brass LF. Interactions of mast cell tryptase with thrombin receptors and PAR-2. J Biol Chem 1997;272:4043–4049.[Abstract/Free Full Text]
  36. Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, Stewart GA. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol 2002;169:4572–4578.[Abstract/Free Full Text]
  37. Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, Thompson PJ. Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. J Allergy Clin Immunol 2001;108:797–803.[CrossRef][Medline]
  38. Ebeling C, Forsythe P, Ng J, Gordon JR, Hollenberg M, Vliagoftis H. Proteinase-activated receptor 2 activation in the airways enhances antigen-mediated airway inflammation and airway hyperresponsiveness through different pathways. J Allergy Clin Immunol 2005;115:623–630.[CrossRef][Medline]
  39. De Campo BA, Henry PJ. Stimulation of protease-activated receptor-2 inhibits airway eosinophilia, hyperresponsiveness and bronchoconstriction in a murine model of allergic inflammation. Br J Pharmacol 2005;144:1100–1108.[CrossRef][Medline]
  40. Vancheri C, Mastruzzo C, Sortino MA, Crimi N. The lung as a privileged site for the beneficial actions of PGE2. Trends Immunol 2004;25:40–46.[CrossRef][Medline]
  41. Lan RS, Stewart GA, Goldie RG, Henry PJ. Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice. Am J Physiol Lung Cell Mol Physiol 2004;286:L388–L398.[Abstract/Free Full Text]
  42. Cocks TM, Moffatt JD. Protease-activated receptor-2 (PAR2) in the airways. Pulm Pharmacol Ther 2001;14:183–191.[CrossRef][Medline]
  43. Schmidlin F, Amadesi S, Vidil R, Trevisani M, Martinet N, Caughey G, Tognetto M, Cavallesco G, Mapp C, Geppetti P, et al. Expression and function of proteinase-activated receptor 2 in human bronchial smooth muscle. Am J Respir Crit Care Med 2001;164:1276–1281.[Abstract/Free Full Text]
  44. Miotto D, Hollenberg MD, Bunnett NW, Papi A, Braccioni F, Boschetto P, Rea F, Zuin A, Geppetti P, Saetta M, et al. Expression of protease activated receptor-2 (PAR-2) in central airways of smokers and non-smokers. Thorax 2002;57:146–151.[Abstract/Free Full Text]
  45. Roche N, Stirling RG, Lim S, Oliver BG, Oates T, Jazrawi E, Caramori G, Chung KF. Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages. J Allergy Clin Immunol 2003;111:367–373.[CrossRef][Medline]
  46. Howells GL, Macey MG, Chinni C, Hou L, Fox MT, Harriott P, Stone SR. Proteinase-activated receptor-2: expression by human neutrophils. J Cell Sci 1997;110:881–887.[Abstract]
  47. Ricciardolo FL, Steinhoff M, Amadesi S, Guerrini R, Tognetto M, Trevisani M, Creminon C, Bertrand C, Bunnett NW, Fabbri LM, et al. Presence and bronchomotor activity of protease-activated receptor-2 in guinea pig airways. Am J Respir Crit Care Med 2000;161:1672–1680.[Abstract/Free Full Text]
  48. Cottrell GS, Amadesi S, Grady EF, Bunnett NW. Trypsin IV, a novel agonist of protease-activated receptors 2 and 4. J Biol Chem 2004;279:13532–13539.[Abstract/Free Full Text]
  49. Takeuchi T, Harris JL, Huang W, Yan KW, Coughlin SR, Craik CS. Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates. J Biol Chem 2000;275:26333–26342.[Abstract/Free Full Text]
  50. Miki M, Nakamura Y, Takahashi A, Nakaya Y, Eguchi H, Masegi T, Yoneda K, Yasuoka S, Sone S. Effect of human airway trypsin-like protease on intracellular free Ca2+ concentration in human bronchial epithelial cells. J Med Invest 2003;50:95–107.[Medline]
  51. Dulon S, Candé C, Bunnett NW, Hollenberg MD, Chignard M, Pidard D. Proteinase-activated receptor-2 and human lung epithelial cells: disarming by neutrophil serine proteinases. Am J Respir Cell Mol Biol 2003;28:339–346.[Abstract/Free Full Text]
  52. Dulon S, Leduc D, Cottrell GS, D'Alayer J, Hansen KK, Bunnett NW, Hollenberg MD, Pidard D, Chignard M. Pseudomonas aeruginosa elastase disables PAR2 in respiratory epithelial cells. Am J Respir Cell Mol Biol 2005;32:411–419.[Abstract/Free Full Text]
  53. Ubl JJ, Grishina ZV, Sukhomlin TK, Welte T, Sedehizade F, Reiser G. Human bronchial epithelial cells express PAR-2 with different sensitivity to thermolysin. Am J Physiol Lung Cell Mol Physiol 2002;282:L1339–L1348.[Abstract/Free Full Text]
  54. Renesto P, Si-Tahar M, Moniatte M, Balloy V, Van Dorsselaer A, Pidard D, Chignard M. Specific inhibition of thrombin-induced cell activation by the neutrophil proteinases elastase, cathepsin G, and proteinase 3: evidence for distinct cleavage sites within the aminoterminal domain of the thrombin receptor. Blood 1997;89:1944–1953.[Abstract/Free Full Text]
  55. Loew D, Perrault C, Morales M, Moog S, Ravanat C, Schuhler S, Arcone R, Pietropaolo C, Cazenave JP, van Dorsselaer A, et al. Proteolysis of the exodomain of recombinant protease-activated receptors: prediction of receptor activation or inactivation by MALDI mass spectrometry. Biochemistry 2000;39:10812–10822.[CrossRef][Medline]
  56. Uehara A, Muramoto K, Takada H, Sugawara S. Neutrophil serine proteinases activate human nonepithelial cells to produce inflammatory cytokines through protease-activated receptor 2. J Immunol 2003;170:5690–5696.[Abstract/Free Full Text]
  57. Compton SJ, Renaux B, Wijesuriya SJ, Hollenberg MD. Glycosylation and the activation of proteinase-activated receptor 2 (PAR(2)) by human mast cell tryptase. Br J Pharmacol 2001;134:705–718.[CrossRef][Medline]
  58. Compton SJ, Sandhu S, Wijesuriya SJ, Hollenberg MD. Glycosylation of human proteinase-activated receptor-2 (hPAR2): role in cell surface expression and signalling. Biochem J 2002;368:495–505.[CrossRef][Medline]
  59. Uehara A, Sugawara S, Muramoto K, Takada H. Activation of human oral epithelial cells by neutrophil proteinase 3 through protease-activated receptor-2. J Immunol 2002;169:4594–4603.[Abstract/Free Full Text]
  60. Moffatt JD, Page CP, Laurent GJ. Shooting for PARs in lung diseases. Curr Opin Pharmacol 2004;4:221–229.[CrossRef][Medline]
  61. Kawabata A, Kawao N. Physiology and pathophysiology of proteinase-activated receptors (PARs): PARs in the respiratory system: cellular signaling and physiological/pathological roles. J Pharmacol Sci 2005;97:20–24.[CrossRef][Medline]



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