title: Influence of influenza A infection on capsaicin-induced responses in murine airways.
abstract: The principal aim of the study was to determine the influence of influenza A virus infection on capsaicin-induced relaxation responses in mouse isolated tracheal segments and clarify the underlying mechanisms. Anesthetized mice were intranasally inoculated with influenza A/PR-8/34 virus (VIRUS) or vehicle (SHAM), and 4 days later tracheal segments were harvested for isometric tension recording and biochemical and histologic analyses. Capsaicin induced dose-dependent relaxation responses in carbachol-contracted SHAM trachea (e.g., 10 μM capsaicin produced 66 ± 4% relaxation; n = 11), which were significantly inhibited by capsazepine [transient receptor potential vanilloid type 1 (TRPV1) antagonist], (2S,3S)-3-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-2-phenylpiperidine hydrochloride (L-733,060) [neurokinin 1 (NK₁) receptor antagonist], indomethacin [cyclooxygenase (COX) inhibitor], and the combination of 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) and 7-[5α-([1S,1α(Z)-biphenyl]-4-ylmethoxy)-2β-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, calcium salt, hydrate (AH23848) [E-prostanoid (EP)₂ and EP₄ receptor antagonists, respectively], indicating that capsaicin-induced relaxation involved the TRPV1-mediated release of substance P (SP), activation of epithelial NK₁ receptors, and production of COX products capable of activating relaxant EP₂/EP₄ receptors. Consistent with this postulate, capsaicin-induced relaxation was associated with the significant release of SP and prostaglandin E₂ (PGE₂) from mouse tracheal segments. As expected, influenza A virus infection was associated with widespread disruption of the tracheal epithelium. Tracheal segments from VIRUS mice responded weakly to capsaicin (7 ± 3% relaxation) and were 25-fold less responsive to SP than tracheas from SHAM mice. In contrast, relaxation responses to exogenous PGE₂ and the β-adrenoceptor agonist isoprenaline were not inhibited in VIRUS trachea. Virus infection was associated with impaired capsaicin-induced release of PGE₂, but the release of SP was not affected. In summary, influenza A virus infection profoundly inhibits capsaicin- and SP-induced relaxation responses, most likely by inhibiting the production of PGE₂.
authors: Pharmacology and Anesthesiology Unit, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
authors: Samuel J
authors: SJ
authors: Taylor
authors: Tracy S
authors: TS
authors: Mann
authors: Peter J
authors: PJ
authors: Henry
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology / Q000821:virology; D009980:Influenza A virus; D007545:Isoproterenol / Q000494:pharmacology; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000473:pathology / Q000821:virology; D013047:Specific Pathogen-Free Organisms; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D044004:Xanthones / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; D016861:Cyclooxygenase Inhibitors; D010880:Piperidines; D011448:Prostaglandin Antagonists; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D044004:Xanthones; C103788:3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D013373:Substance P; C046926:AH 23848; D002217:Carbachol; D015232:Dinoprostone; D007545:Isoproterenol; C071423:capsazepine; D002211:Capsaicin; D007213:Indomethacin