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1 Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; Discilpine of Microbiology, School of Biomedical and Chemical Sciences, University of Western Australia, Perth, Western Australia, Australia
2 Western Australian Institute for Medical Research, University of Western Australia, Perth, Western Australia, Australia; Discilpine of Microbiology, School of Biomedical and Chemical Sciences, University of Western Australia, Perth, Western Australia, Australia
3 Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; Western Australian Institute for Medical Research, University of Western Australia, Perth, Western Australia, Australia
* To whom correspondence should be addressed. E-mail: phenry{at}receptor.pharm.uwa.edu.au.
Protease-activated receptors (PARs) are widely distributed in human airways, and recent evidence indicates a role for PARs in the pathophysiology of inflammatory airways disease. To further investigate the role of PARs in airways disease, the expression and function of PARs in a murine model of respiratory tract viral infection was determined. PAR1, PAR2, PAR3 and PAR4 mRNA and protein were expressed in murine airways, and confocal microscopy revealed colocalization of PAR2 and COX-2 immunostaining in basal tracheal epithelial cells. Elevated levels of PAR immunostaining, which was particularly striking for PAR1 and PAR2, were observed in the airways of influenza A/PR-8/34 virus-infected mice compared to sham-infected mice. Furthermore, increased PAR1 and PAR2 expression was associated with significant changes in in vivo lung function responses. PAR1 agonist peptide potentiated methacholine-induced increases in airways resistance in anaesthetized shaminfected mice (and in indomethacin-treated, virus-infected mice), but no such potentiation was observed in virus-infected mice. PAR2 agonist peptide transiently inhibited methacholineinduced bronchoconstriction in sham-infected mice, and this effect was prolonged in virusinfected mice. These findings suggest that during viral infection, the upregulation of PARs in the airways is coupled to increased activation of cyclooxygenase and enhanced generation of bronchodilatory prostanoids.
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