科研之友
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摘要
Background: Activation of transient receptor potential vanilloid type 1 (TRPV1) decreases lung ischemiaereperfusion injury (LIRI) in rabbits and rats. Stimulation of alpha 7 nicotinic acetylcholine receptors (alpha 7nAChRs) protects against lung injury. Here we examined whether alpha 7nAChRs contribute to TRPV1-mediated protection against LIRI. Methods: Wild-type (WT) and TRPV1-knockout (KO) mice were subjected to 1-h lung ischemia by clamping left hilum, followed by 2-h reperfusion. WT or KO mice were pretreated with vehicle, TRPV1 agonist capsaicin, TRPV1 antagonist capsazepine, alpha 7nAChR antagonist methyllycaconitine, or alpha 7nAChR agonist PNU-282987. Arterial blood and lung tissues were obtained for blood gas, lung wet-to-dry weight ratio, interleukin (IL) 1 beta, IL6, tumor necrosis factor-alpha (TNF-alpha), apoptosis-related proteins (caspases, Bax, Fas), and pathologic scoring. Results: Capsaicin pretreatment reduced wet-to-dry ratio, pathologic score, alveolar-arterial oxygen gradient (A-aDO(2)), and IL1 beta, IL6, and TNF alpha levels in WT mice, with no effects in KO mice. This reduction was reversed by TRPV1 blockade. Furthermore, alpha 7nAChR blockade before capsaicin exacerbated LIRI as evidenced by enhanced alveolar-arterial oxygen gradient, pathologic score, and IL1 beta, IL6, and TNF alpha levels, while alpha 7nAChR agonist pretreatment under TRPV1 blockade showed opposite changes. Capsaicin also decreased cleaved caspase-3, caspase-3/9, and Bax protein expression, effects abolished by TRPV1 blockade. Similarly, alpha 7nAChR blockade diminished capsaicin-induced downregulation of apoptotic proteins, and alpha 7nAChR activation decreased expression levels even under TRPV1 blockade. Conclusions: TRPV1 activation alleviates LIRI, partially dependent on alpha 7nAChR activity. The alpha 7nAChR stimulation with or without existence of TRPV1 alleviates LIRI. Thus, alpha 7nAChR is involved in the pathway of TRPV1-mediated protection against LIRI and the specific mechanism remains to be revealed.
