A protective role for protease-activated receptors in the airways

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 epithelium. As the airway epithelium is morphologically similar and also expresses one of these receptors, PAR2, and is a major source of PGE2, 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.

A synonymous variation in protease-activated receptor-2 is associated with atopy in Korean children

“…14,15,19,[23][24][25] Most studies show that PAR-2 has a proinflammatory effect via PAR-2 agonist experiments, but some reports suggest that PAR-2 can have a protective effect against inflammation. 18,[24][25][26][27][28] Clearly, the role(s) of PAR-2 in inflammation is still not fully understood. Other recent results include the finding of increased PAR-2 expression in respiratory epithelial cells from patients with asthma.…”

“…25 However, there is also evidence that PAR-2 may play a protective role in the airways. PAR-2 activation induces bronchodilation 18,26,27 and attenuates antigen-induced bronchoconstriction in animal models. 28 We conducted an association study of PAR-2 polymorphisms with susceptibility to atopy in a Korean childhood cohort.…”

“…[14][15][16] The human PAR-2 gene is located in 5q13, tightly clustered with PAR-1 and -3 while PAR-4 is located separately at 19p12. 17 PAR-2 is expressed in human lung epithelial cells, airway smooth muscle, 18 and fibroblasts 19 as well as in vascular smooth muscle and endothelial cells. 20 PAR-2 activation on airway epithelial cells causes the release of prostaglandin E2, 18 GM-CSF, eotaxin, 21 and matrix metalloproteinase-9.…”

“…17 PAR-2 is expressed in human lung epithelial cells, airway smooth muscle, 18 and fibroblasts 19 as well as in vascular smooth muscle and endothelial cells. 20 PAR-2 activation on airway epithelial cells causes the release of prostaglandin E2, 18 GM-CSF, eotaxin, 21 and matrix metalloproteinase-9. 22 PAR-2 expression is increased in respiratory epithelial cells of patients with asthma, 23 but the physiological role of PAR-2 in the airways remains unclear.…”

Protease-Activated Receptor 2 Mediates Eosinophil Infiltration and Hyperreactivity in Allergic Inflammation of the Airway

“…However, there is controversy about whether PAR2 agonists protect or promote airway inflammation. In support of a protective role are observations that PAR2 agonists induce an eicosanoid-dependent bronchodilation in rats, mice, and guinea pigs (8,12,13), and that intranasal administration of a PAR2 agonist in mice reduces the infiltration of neutrophils into bronchoalveolar lavage (BAL) after treatment with LPS (11). PAR2 agonists also relax the guinea pig trachea and human bronchi by releasing eicosanoids and NO from the epithelium (9,10).…”