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A protective role for protease-activated receptors in the airways

Nature volume 398, pages 156–160 (1999)Cite this article

Abstract

The protection of cells in the upper intestine against digestion by pancreatic trypsin depends on the prostanoid prostaglandin E2 (PGE2) and is mediated by protease-activated receptors in the epithelium1,2. As the airway epithelium is morphologically similar and also expresses one of these receptors, PAR2 (ref. 3), and is a major source of PGE2 (ref. 4), we reasoned that bronchial epithelial PAR2 might also participate in prostanoid-dependent cytoprotection in the airways. Here we show that activation of PAR2, which co-localizes immunohistochemically with trypsin(ogen) in airway epithelium, causes the relaxation of airway preparations from mouse, rat, guinea-pig and humans by the release of a cyclooxygenase product from the epithelium. This physiological protective response in isolated airways also occurred in anaesthetized rats, where activation of PAR2 caused a marked and prolonged inhibition of bronchoconstriction. After desensitization of PAR2, the response to trypsin recovered rapidly by mechanisms dependent on de novo synthesis and trafficking of proteins. Our results indicate that trypsin released from the epithelium can initiate powerful bronchoprotection in the airways by activation of epithelial PAR2.

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Figure 1: Immunohistochemical localization of PAR2 in mouse bronchi and demonstration that PAR2 and PAR1 mediate epithelium-dependent relaxation in isolated rings of this tissue.
Figure 2: Mechanisms of PAR-mediated bronchial relaxation.
Figure 3: Recovery of responsiveness to PAR2 activation after trypsin desensitization in the mouse bronchus.
Figure 4: Demonstration that the PAR2-activating peptide SLIGRL-NH2 inhibits bronchoconstriction in vivo.
Figure 5: Dual immunohistochemical localization of PAR2 (green) and trypsin(ogen) (red) within the epithelium of a 3-µm-thick cross-section of human intrapulmonary bronchiole.

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Acknowledgements

This work was supported by the NHMRC of Australia. We thank V. Sozzi and J.Rogers for technical assistance; J. Morrison, M. O'Bryan, B. Major and S. Selemidis for help with in situ hybridization and for comments; N. Bunnett for mouse PAR2 antibody; A. Hughes and A. Hunt-Sturman for synthesis of some of the peptides; and J. Tatoulis and staff of the Royal Melbourne Hospital, Melbourne for their help in obtaining preparations of human airway and financial support for J.D.M.

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Authors and Affiliations

  1. Departments of Pharmacology,

    T. M. Cocks, B. Fong, J. M. Chow, G. P. Anderson, J. R. Hamilton & J. D. Moffatt

  2. Departments of Medicine, University of Melbourne, Parkville, 3052, Victoria, Australia

    A. G. Frauman

  3. Department of Pharmacology, University of Western Australia, Perth, 6907, Western Australia, Australia

    R. G. Goldie, P. J. Henry & M. J. Carr

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Correspondence to T. M. Cocks.

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Cocks, T., Fong, B., Chow, J. et al. A protective role for protease-activated receptors in the airways. Nature 398, 156–160 (1999). https://doi.org/10.1038/18223

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