Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice.
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.
Lan
Rommel S
RS
School of Medicine and Pharmacology, Faculty of Medicine and Dentistry, University of Western Australia, Perth, 6009 W. A., Australia.
Stewart
Geoffrey A
GA
Goldie
Roy G
RG
Henry
Peter J
PJ
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
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