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[摘要]：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 mu M 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 (NK 1) receptor antagonist], indomethacin [cyclooxygenase (COX) inhibitor], and the combination of 6-isopropoxy9- oxoxanthene-2-carboxylic acid (AH6809) and 7-[5 alpha-([1S, 1 alpha(Z)-biphenyl]-4-ylmethoxy)-2 beta-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, calcium salt, hydrate (AH23848) [E-prostanoid (EP)(2) and EP(4) receptor antagonists, respectively], indicating that capsaicin-induced relaxation involved the TRPV1-mediated release of substance P (SP), activation of epithelial NK 1 receptors, and production of COX products capable of activating relaxant EP(2)/EP(4) receptors. Consistent with this postulate, capsaicin-induced relaxation was associated with the significant release of SP and prostaglandin E(2) (PGE(2)) 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 PGE(2) and the beta-adrenoceptor agonist isoprenaline were not inhibited in VIRUS trachea. Virus infection was associated with impaired capsaicin-induced release of PGE(2), 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 PGE(2). |
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