Background: Proteinase-activated receptors (PARs; PAR 1-4 ) that can be activated by serine proteinases such as thrombin and neutrophil catepsin G are known to contribute to the pathogenesis of various pulmonary diseases including fibrosis. Among these PARs, especially PAR 4 , a newly identified subtype, is highly expressed in the lung. Here, we examined whether PAR 4 stimulation plays a role in the formation of fibrotic response in the lung, through alveolar epithelialmesenchymal transition (EMT) which contributes to the increase in myofibroblast population.

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The protease-activated receptor-2 (PAR-2) has been implicated in airway inflammation. Here, we examined the interaction between PAR-2 and lipopolysaccharide (LPS), a major proinflammatory factor, using cultured guinea pig tracheal epithelial cells. In fura2-loaded cells, LPS (1 microg/ml) transiently increased intracellular Ca(2+) concentrations ([Ca(2+)]i), this effect being abolished by a Ca(2+) channel blocker, verapamil, and Ca(2+) removal. Prestimulation of PAR-2 with trypsin (0.1-1 U/ml) or an agonist peptide (SLIGRL-NH(2), 1 microM) for 60 min inhibited the LPS-induced [Ca(2+)]i increase. Such an inhibitory effect of trypsin was abolished by inhibitors of protein kinase C (PKC), chelerythrine and staurosporine. A PKC activator, phorbol 12,13-dibutylate, also reduced the LPS response. Trypsin also inhibited a transient increase in [Ca(2+)]i caused by a Ca(2+) channel opener, Bay K 8644. When the trypsin-pretreated cells were incubated in normal buffer for 10-60 min before LPS exposure, the effect of trypsin on the Ca(2+) response to LPS diminished in a time-dependent manner. Such a recovery was slowed by incubation with a protein phosphatase inhibitor, okadaic acid. Further, trypsin induced sustained activations of PKCalpha and -epsilon. Thus, PAR-2 stimulation reduced the epithelial cell response to LPS, probably through the inactivation of Ca(2+) channels via PKC-mediated phosphorylation.