七氟烷调控Nrf2在改善脓毒症所致膈肌功能障碍中的作用及分子机制

脓毒症所致膈肌功能障碍（SIDD）可致患者呼吸衰竭、呼吸机撤机困难甚至死亡，临床上缺乏治疗手段。申请人致力于SIDD的机制研究，为SIDD治疗手段的探索提供了基础。前期实验发现七氟烷可以改善SIDD，并初步提示与其激活脓毒症膈肌Nrf2，增强线粒体呼吸，减轻铁超载和脂质过氧化损伤，增加还原型谷胱甘肽水平和谷胱甘肽过氧化物酶4表达有关。鉴于铁聚集、脂质过氧化损伤、谷胱甘肽代谢紊乱是铁死亡的重要标记，我们推测七氟烷可能通过激活Nrf2发挥抗氧化应激、抑制铁死亡及增强线粒体呼吸实现对SIDD的保护作用。本项目拟以此为基础，将进一步阐明七氟烷如何保护脓毒症膈肌功能；探讨其起保护作用的最适浓度；探索七氟烷发挥保护作用的通路机制并进行临床效果验证。作为临床常用麻醉药物，七氟烷“老药新用”极大方便临床推广。本课题的开展将为SIDD的临床治疗提供新的、切实可行的措施和全新的干预靶点，推动SIDD治疗进程。

Sepsis-induced diaphragmatic dysfunction (SIDD) can lead to respiratory failure, weaning difficulties, and even death. But there is no effective treatments in clinic. The applicant is committed to the study of SIDD mechanisms, which provides the basis for the exploration of SIDD treatments. Our preliminary study found that sevoflurane can improve SIDD. Such effects might be associated with enhanced mitochondrial respiration, reduced iron overload and lipid peroxidation damage, increased alleviation of glutathione (GSH) level and glutathione peroxidase 4 (GPX4) expression in the diaphragm with sepsis via activating Nrf2. Since iron aggregation, lipid peroxidation damage and glutathione metabolism disorder are hallmarks of ferroptosis, we speculated that sevoflurane may play a protective role in SIDD via exerting antioxidant stress, inhibiting ferroptosis and enhancing mitochondrial respiration by activating Nrf2. Based on this, the project will further clarify how sevoflurane protects SIDD and its optimal concentration for SIDD protection. We will also explore the pathway of how the sevoflurane protect SIDD and verify the protective effects of sevoflurane in clinic. Given that sevoflurane is widely used as an anaesthetic, the new usage of this drug is convenient for clinical application. This study aim to develop novel strategies and identify new molecular targets for the treatment of SIDD.