Skip to main content
NCBI home page
Thorax logoLink to Thorax
. 2002 Feb;57(2):146–151. doi: 10.1136/thorax.57.2.146

Expression of protease activated receptor-2 (PAR-2) in central airways of smokers and non-smokers

D Miotto 1, M Hollenberg 1, N Bunnett 1, A Papi 1, F Braccioni 1, P Boschetto 1, F Rea 1, A Zuin 1, P Geppetti 1, M Saetta 1, P Maestrelli 1, L Fabbri 1, C Mapp 1
PMCID: PMC1746249  PMID: 11828045

Abstract

Background: Protease activated receptor-2 (PAR-2) is a transmembrane G protein coupled receptor preferentially activated by trypsin and tryptase. The protease activated receptors play an important role in most components of injury responses including cell proliferation, migration, matrix remodelling, and inflammation. Cigarette smoking causes an inflammatory process in the central airways, peripheral airways, lung parenchyma, and adventitia of pulmonary arteries.

Methods: To quantify the expression of PAR-2 in the central airways of smokers and non-smokers, surgical specimens obtained from 30 subjects undergoing lung resection for localised pulmonary lesions (24 with a history of cigarette smoking and six non-smoking control subjects) were examined. Central airways were immunostained with an antiserum specific for PAR-2 and PAR-2 expression was quantified using light microscopy and image analysis.

Results: PAR-2 expression was found in bronchial smooth muscle, epithelium, glands, and in the endothelium and smooth muscle of bronchial vessels. PAR-2 expression was similar in the central airways of smokers and non-smokers. When smokers were divided according to the presence of symptoms of chronic bronchitis and chronic airflow limitation, PAR-2 expression was increased in smooth muscle (median 3.8 (interquartile range 2.9–5.8) and 1.4 (1.07–3.4) respectively); glands (33.3 (18.2–43.8) and 16.2 (11.5–22.2), respectively); and bronchial vessels (54.2 (48.7–56.8) and 40.0 (36–40.4), respectively) of smokers with symptoms of chronic bronchitis with normal lung function compared with smokers with chronic airflow limitation (COPD), but the increase was statistically significant (p<0.005) only for bronchial vessels.

Conclusions: PAR-2 is present in bronchial smooth muscle, glands, and bronchial vessels of both smokers and non-smokers. An increased expression of PAR-2 was found in bronchial vessels of patients with bronchitis compared with those with COPD.

Full Text

The Full Text of this article is available as a PDF (193.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Al-Ani B., Saifeddine M., Kawabata A., Renaux B., Mokashi S., Hollenberg M. D. Proteinase-activated receptor 2 (PAR(2)): development of a ligand-binding assay correlating with activation of PAR(2) by PAR(1)- and PAR(2)-derived peptide ligands. J Pharmacol Exp Ther. 1999 Aug;290(2):753–760. [PubMed] [Google Scholar]
  2. Berger P., Perng D. W., Thabrew H., Compton S. J., Cairns J. A., McEuen A. R., Marthan R., Tunon De Lara J. M., Walls A. F. Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells. J Appl Physiol (1985) 2001 Sep;91(3):1372–1379. doi: 10.1152/jappl.2001.91.3.1372. [DOI] [PubMed] [Google Scholar]
  3. Bohm S. K., Kong W., Bromme D., Smeekens S. P., Anderson D. C., Connolly A., Kahn M., Nelken N. A., Coughlin S. R., Payan D. G. Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J. 1996 Mar 15;314(Pt 3):1009–1016. doi: 10.1042/bj3141009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cocks T. M., Fong B., Chow J. M., Anderson G. P., Frauman A. G., Goldie R. G., Henry P. J., Carr M. J., Hamilton J. R., Moffatt J. D. A protective role for protease-activated receptors in the airways. Nature. 1999 Mar 11;398(6723):156–160. doi: 10.1038/18223. [DOI] [PubMed] [Google Scholar]
  5. Cocks T. M., Moffatt J. D. Protease-activated receptors: sentries for inflammation? Trends Pharmacol Sci. 2000 Mar;21(3):103–108. doi: 10.1016/s0165-6147(99)01440-6. [DOI] [PubMed] [Google Scholar]
  6. Compton S. J., Cairns J. A., Holgate S. T., Walls A. F. The role of mast cell tryptase in regulating endothelial cell proliferation, cytokine release, and adhesion molecule expression: tryptase induces expression of mRNA for IL-1 beta and IL-8 and stimulates the selective release of IL-8 from human umbilical vein endothelial cells. J Immunol. 1998 Aug 15;161(4):1939–1946. [PubMed] [Google Scholar]
  7. D'Andrea M. R., Derian C. K., Leturcq D., Baker S. M., Brunmark A., Ling P., Darrow A. L., Santulli R. J., Brass L. F., Andrade-Gordon P. Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues. J Histochem Cytochem. 1998 Feb;46(2):157–164. doi: 10.1177/002215549804600204. [DOI] [PubMed] [Google Scholar]
  8. D'Andrea M. R., Rogahn C. J., Andrade-Gordon P. Localization of protease-activated receptors-1 and -2 in human mast cells: indications for an amplified mast cell degranulation cascade. Biotech Histochem. 2000 Mar;75(2):85–90. doi: 10.3109/10520290009064152. [DOI] [PubMed] [Google Scholar]
  9. Damiano B. P., D'Andrea M. R., de Garavilla L., Cheung W. M., Andrade-Gordon P. Increased expression of protease activated receptor-2 (PAR-2) in balloon-injured rat carotid artery. Thromb Haemost. 1999 May;81(5):808–814. [PubMed] [Google Scholar]
  10. Déry O., Corvera C. U., Steinhoff M., Bunnett N. W. Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am J Physiol. 1998 Jun;274(6 Pt 1):C1429–C1452. doi: 10.1152/ajpcell.1998.274.6.C1429. [DOI] [PubMed] [Google Scholar]
  11. Hollenberg M. D. Protease-activated receptors: PAR4 and counting: how long is the course? Trends Pharmacol Sci. 1999 Jul;20(7):271–273. doi: 10.1016/s0165-6147(99)01333-4. [DOI] [PubMed] [Google Scholar]
  12. Hwa J. J., Ghibaudi L., Williams P., Chintala M., Zhang R., Chatterjee M., Sybertz E. Evidence for the presence of a proteinase-activated receptor distinct from the thrombin receptor in vascular endothelial cells. Circ Res. 1996 Apr;78(4):581–588. doi: 10.1161/01.res.78.4.581. [DOI] [PubMed] [Google Scholar]
  13. Kawabata A., Kuroda R., Minami T., Kataoka K., Taneda M. Increased vascular permeability by a specific agonist of protease-activated receptor-2 in rat hindpaw. Br J Pharmacol. 1998 Oct;125(3):419–422. doi: 10.1038/sj.bjp.0702063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kawabata A., Morimoto N., Nishikawa H., Kuroda R., Oda Y., Kakehi K. Activation of protease-activated receptor-2 (PAR-2) triggers mucin secretion in the rat sublingual gland. Biochem Biophys Res Commun. 2000 Apr 2;270(1):298–302. doi: 10.1006/bbrc.2000.2404. [DOI] [PubMed] [Google Scholar]
  15. Kong W., McConalogue K., Khitin L. M., Hollenberg M. D., Payan D. G., Böhm S. K., Bunnett N. W. Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8884–8889. doi: 10.1073/pnas.94.16.8884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Koshikawa N., Nagashima Y., Miyagi Y., Mizushima H., Yanoma S., Yasumitsu H., Miyazaki K. Expression of trypsin in vascular endothelial cells. FEBS Lett. 1997 Jun 16;409(3):442–448. doi: 10.1016/s0014-5793(97)00565-6. [DOI] [PubMed] [Google Scholar]
  17. Lan R. S., Stewart G. A., Henry P. J. Modulation of airway smooth muscle tone by protease activated receptor-1,-2,-3 and -4 in trachea isolated from influenza A virus-infected mice. Br J Pharmacol. 2000 Jan;129(1):63–70. doi: 10.1038/sj.bjp.0703007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Magazine H. I., King J. M., Srivastava K. D. Protease activated receptors modulate aortic vascular tone. Int J Cardiol. 1996 Apr 26;53 (Suppl):S75–S80. doi: 10.1016/0167-5273(96)02569-7. [DOI] [PubMed] [Google Scholar]
  19. Molino M., Woolkalis M. J., Reavey-Cantwell J., Praticó D., Andrade-Gordon P., Barnathan E. S., Brass L. F. Endothelial cell thrombin receptors and PAR-2. Two protease-activated receptors located in a single cellular environment. J Biol Chem. 1997 Apr 25;272(17):11133–11141. doi: 10.1074/jbc.272.17.11133. [DOI] [PubMed] [Google Scholar]
  20. Nguyen T. D., Moody M. W., Steinhoff M., Okolo C., Koh D. S., Bunnett N. W. Trypsin activates pancreatic duct epithelial cell ion channels through proteinase-activated receptor-2. J Clin Invest. 1999 Jan;103(2):261–269. doi: 10.1172/JCI2539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nystedt S., Emilsson K., Larsson A. K., Strömbeck B., Sundelin J. Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2. Eur J Biochem. 1995 Aug 15;232(1):84–89. doi: 10.1111/j.1432-1033.1995.tb20784.x. [DOI] [PubMed] [Google Scholar]
  22. Nystedt S., Ramakrishnan V., Sundelin J. The proteinase-activated receptor 2 is induced by inflammatory mediators in human endothelial cells. Comparison with the thrombin receptor. J Biol Chem. 1996 Jun 21;271(25):14910–14915. doi: 10.1074/jbc.271.25.14910. [DOI] [PubMed] [Google Scholar]
  23. Peinado V. I., Barberá J. A., Abate P., Ramírez J., Roca J., Santos S., Rodriguez-Roisin R. Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999 May;159(5 Pt 1):1605–1611. doi: 10.1164/ajrccm.159.5.9807059. [DOI] [PubMed] [Google Scholar]
  24. Pesci A., Rossi G. A., Bertorelli G., Aufiero A., Zanon P., Olivieri D. Mast cells in the airway lumen and bronchial mucosa of patients with chronic bronchitis. Am J Respir Crit Care Med. 1994 May;149(5):1311–1316. doi: 10.1164/ajrccm.149.5.8173772. [DOI] [PubMed] [Google Scholar]
  25. Ricciardolo F. L., Steinhoff M., Amadesi S., Guerrini R., Tognetto M., Trevisani M., Creminon C., Bertrand C., Bunnett N. W., Fabbri L. M. Presence and bronchomotor activity of protease-activated receptor-2 in guinea pig airways. Am J Respir Crit Care Med. 2000 May;161(5):1672–1680. doi: 10.1164/ajrccm.161.5.9907133. [DOI] [PubMed] [Google Scholar]
  26. Saetta M., Turato G., Zuin R. Structural basis for airflow limitation in chronic obstructive pulmonary disease. Sarcoidosis Vasc Diffuse Lung Dis. 2000 Oct;17(3):239–245. [PubMed] [Google Scholar]
  27. Shu S. Y., Ju G., Fan L. Z. The glucose oxidase-DAB-nickel method in peroxidase histochemistry of the nervous system. Neurosci Lett. 1988 Feb 29;85(2):169–171. doi: 10.1016/0304-3940(88)90346-1. [DOI] [PubMed] [Google Scholar]
  28. Steinhoff M., Vergnolle N., Young S. H., Tognetto M., Amadesi S., Ennes H. S., Trevisani M., Hollenberg M. D., Wallace J. L., Caughey G. H. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med. 2000 Feb;6(2):151–158. doi: 10.1038/72247. [DOI] [PubMed] [Google Scholar]
  29. Vergnolle N., Hollenberg M. D., Sharkey K. A., Wallace J. L. Characterization of the inflammatory response to proteinase-activated receptor-2 (PAR2)-activating peptides in the rat paw. Br J Pharmacol. 1999 Jul;127(5):1083–1090. doi: 10.1038/sj.bjp.0702634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vliagoftis H., Befus A. D., Hollenberg M. D., Moqbel R. Airway epithelial cells release eosinophil survival-promoting factors (GM-CSF) after stimulation of proteinase-activated receptor 2. J Allergy Clin Immunol. 2001 Apr;107(4):679–685. doi: 10.1067/mai.2001.114245. [DOI] [PubMed] [Google Scholar]
  31. Vliagoftis H., Schwingshackl A., Milne C. D., Duszyk M., Hollenberg M. D., Wallace J. L., Befus A. D., Moqbel R. Proteinase-activated receptor-2-mediated matrix metalloproteinase-9 release from airway epithelial cells. J Allergy Clin Immunol. 2000 Sep;106(3):537–545. doi: 10.1067/mai.2000.109058. [DOI] [PubMed] [Google Scholar]
  32. al-Ani B., Saifeddine M., Hollenberg M. D. Detection of functional receptors for the proteinase-activated-receptor-2-activating polypeptide, SLIGRL-NH2, in rat vascular and gastric smooth muscle. Can J Physiol Pharmacol. 1995 Aug;73(8):1203–1207. doi: 10.1139/y95-172. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES