1. Departments of Pharmacology and
2. Departments of Medicine, University of Melbourne, Parkville, Victoria 3052, Australia
3. Department of Pharmacology, University of Western Australia, Perth, Western Australia 6907, Australia

Correspondence to: T. M. Cocks¹ Correspondence and requests for materials should be addressed to T.C. (e-mail: Email: t.cocks@pharmacology.unimelb.edu.au)

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.