Abstract：
Background: Lung ischemia-reperfusion injury (LIRI) remains the major cause of primary lung dysfunction after lung transplantation. Diabetes mellitus (DM) is an independent risk factor for morbidity and mortality following lung transplantation. Mitochondrial dysfunction is recognized as a key mediator in the pathogenesis of diabetic LIRI. Melatonin has been reported to be a safe and potent preserving mitochondrial function agent. This study aimed at investigating the potential therapeutic effect and mechanisms of melatonin on diabetic LIRI. Methods: High-fat-diet-fed streptozotocin-induced type 2 diabetic rats were exposed to melatonin, with or without administration of the SIRT3 short hairpin ribonucleic acid (shRNA) plasmid following a surgical model of ischemia-reperfusion injury of the lung. Lung function, inflammation, oxidative stress, cell apoptosis, and mitochondrial function were examined. Results: The SIRT3 signaling and mitophagy were suppressed following diabetic LIRI. Treatment with melatonin markedly induced mitophagy and restored SIRT3 expression. Melatonin treatment also attenuated subsequent diabetic LIRI by improving lung functional recovery, suppressing inflammation, decreasing oxidative damage, diminishing cell apoptosis, and preserving mitochondrial function. However, either administration of SIRT3 shRNA or an autophagy antagonist 3-methyladenine (3-MA) suppressing mitophagy, and compromised the protective action of melatonin. Conclusion: Data indicated that melatonin attenuates diabetic LIRI through activation of SIRT3 signaling-mediated mitophagy.
摘要：
背景:肺缺血再灌注损伤(LIRI)仍然是肺移植后原发性肺功能障碍的主要原因。糖尿病（DM）是肺移植后发病率和死亡率的独立危险因素。线粒体功能障碍被认为是糖尿病LIRI发病机制中的关键介质。据报道，褪黑激素是一种安全有效的线粒体功能保护剂。本研究旨在探讨褪黑素对糖尿病LIRI的潜在治疗作用及其机制。方法：高脂饮食喂养链脲佐菌素诱导的2型糖尿病大鼠暴露于褪黑素，在肺缺血再灌注损伤的手术模型后，有或没有施用SIRT3短发夹核糖核酸（shRNA）质粒。肺功能,炎症,氧化应激，细胞凋亡，和线粒体功能进行了检查。结果：SIRT3信号传导和线粒体自噬在糖尿病LIRI后被抑制。用褪黑激素处理显著诱导线粒体自噬并恢复SIRT3表达。褪黑素治疗还通过改善肺功能恢复来减轻随后的糖尿病LIRI，抑制炎症，减少氧化损伤，减少细胞凋亡，并保留线粒体功能。然而,给予SIRT3shRNA或自噬拮抗剂3-甲基腺嘌呤（3-MA）抑制线粒体自噬，并损害了褪黑激素的保护作用。结论：数据表明褪黑素通过激活SIRT3信号介导的线粒体自噬来减轻糖尿病性LIRI。
