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 M capsaicin produced 66 Ϯ 4% relaxation; n ϭ 11), which were significantly inhibited by capsazepine 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 Ϯ 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 ␤-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 .

Influenza A infection attenuates relaxation responses of mouse tracheal smooth muscle evoked by acrolein

“…More importantly, relaxation responses elicited by exogenous PGE 2 and isoprenaline, which activate EP 2 receptors and b-adrenoceptors expressed on smooth muscle cells respectively, were not reduced by Influenza A infection. In fact, in accordance with previous observations [33], exogenous PGE 2 exhibited a greater potency in VIRUS segments compared to SHAM segments, the precise mechanisms underlying which require further elucidation. However, what is clear is that this heightened sensitivity exhibited by VIRUS-infected mice to PGE 2 was insufficient in compensating for the marked reduction in the capacity of epithelial cells to generate PGE 2 in response to acrolein, resulting in an overall attenuation of the relaxation response to acrolein.…”

“…This is likely due to the presence of fewer epithelial cells resulting from virusinduced epithelial luminal shedding. In addition, attenuation in both relaxation responses and PGE 2 release were mirrored in response to SP in VIRUS segments, consistent with previous observations [33]. Therefore Influenza A-induced epithelial disruption appears to be a major contributing factor in the attenuation of relaxation responses evoked by acrolein.…”

“…However, the particular strain of Influenza A investigated in the present study (H1N1) has not been demonstrated to exhibit a great degree of neuropathogenicity in several mammalian species, including primates and mice [2]. Consistent with this, the capacity of Influenza A/PR-8/34 (H1N1)-infected mice to generate and release SP from sensory C-fibres was not found to be adversely affected by viral infection [33]. Thus, attenuation of acroleininduced relaxation of tracheal smooth muscle via neuropathogenic effects of Influenza A appears unlikely in this context.…”

“…Such histopathologic changes of Influenza A-infected tracheal epithelium were observed in the current study, with desquamation and regional epithelial shedding likely having functional consequences on the epithelium. A dependency of smooth muscle relaxation responses on an intact epithelium has been unequivocally demonstrated for several relaxants including capsaicin [20,33] and SP [34,35] whereby relaxation responses were substantially diminished or completely abolished by either mechanical or viral-induced disruption of the epithelium. In view of the intermediary role of the epithelium in acrolein-induced relaxation responses, in combination with the well-established effects of Influenza A on the epithelium, the airway epithelium represents an obvious target for modulation of relaxation responses by Influenza A.…”

Cellular Mechanism Underlying Formaldehyde-Stimulated Cl− Secretion in Rat Airway Epithelium

“…Our model also suggests an SP related inflammatory pathway at the high concentration of FA since SP is a well-known inflammatory factor. On the other hand, SP can activate NK1R in epithelium, evoking COX, which results in the generation of PGE 2 and activates EP 2/4 receptors in airway smooth muscle, leading to an increase in cAMP [42]. This study provides a possible pathway in our model that PGE 2 may also activate EP 2/4 receptors and increase the level of cAMP in epithelium to activate CFTR.…”