title: Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice.
abstract: Protease-activated receptors (PARs) are widely distributed in human airways, and recent evidence indicates a role for PARs in the pathophysiology of inflammatory airway disease. To further investigate the role of PARs in airway disease, we determined the expression and function of PARs in a murine model of respiratory tract viral infection. PAR-1, PAR-2, PAR-3, and PAR-4 mRNA and protein were expressed in murine airways, and confocal microscopy revealed colocalization of PAR-2 and cyclooxygenase (COX)-2 immunostaining in basal tracheal epithelial cells. Elevated levels of PAR immunostaining, which was particularly striking for PAR-1 and PAR-2, were observed in the airways of influenza A/PR-8/34 virus-infected mice compared with sham-infected mice. Furthermore, increased PAR-1 and PAR-2 expression was associated with significant changes in in vivo lung function responses. PAR-1 agonist peptide potentiated methacholine-induced increases in airway resistance in anesthetized sham-infected mice (and in indomethacin-treated, virus-infected mice), but no such potentiation was observed in virus-infected mice. PAR-2 agonist peptide transiently inhibited methacholine-induced bronchoconstriction in sham-infected mice, and this effect was prolonged in virus-infected mice. These findings suggest that during viral infection, the upregulation of PARs in the airways is coupled to increased activation of COX and enhanced generation of bronchodilatory prostanoids.
authors: School of Medicine and Pharmacology, Faculty of Medicine and Dentistry, University of Western Australia, Perth, 6009 W. A., Australia.
authors: Rommel S
authors: RS
authors: Lan
authors: Geoffrey A
authors: GA
authors: Stewart
authors: Roy G
authors: RG
authors: Goldie
authors: Peter J
authors: PJ
authors: Henry
mesh_terms: D000403:Airway Resistance / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005690:Galactose / Q000378:metabolism; D015870:Gene Expression; D007213:Indomethacin / Q000494:pharmacology; D009980:Influenza A virus; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000503:physiopathology*; D010455:Peptides / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D044463:Receptor, PAR-1 / Q000819:agonists / Q000235:genetics*; D044464:Receptor, PAR-2 / Q000235:genetics*; D044462:Receptors, Proteinase-Activated / Q000235:genetics; D020545:Respiratory Mucosa / Q000502:physiology / Q000821:virology*; D014132:Trachea / Q000502:physiology / Q000821:virology
chemical_list: D016085:Bronchoconstrictor Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D010455:Peptides; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D044462:Receptors, Proteinase-Activated; C481941:protease-activated receptor 3, mouse; C481942:protease-activated receptor 4, mouse; D016210:Methacholine Chloride; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005690:Galactose; D007213:Indomethacin