Li Shaoping, Luo Guanguan, Zeng Rong, Lin Lian, Zou Xingnan, Yan Yu, Ma Haoli, Xia Jian, Zhao Yan, Zhou Xianlong
Emergency Center, Hubei Clinical Research Center for Emergency and Resuscitation, Zhongnan Hospital of Wuhan University, Wuhan, China.
Front Physiol. 2022 Jun 27;13:897559. doi: 10.3389/fphys.2022.897559. eCollection 2022.
Accumulating evidence indicates that endoplasmic reticulum (ER) stress plays a critical role in the regulation of skeletal muscle mass. In recent years, much attention has been given to ventilator-induced diaphragm dysfunction (VIDD) because it strongly impacts the outcomes of critically ill patients. Current evidence suggests that the enhancement of oxidative stress is essential for the development of VIDD, but there are no data on the effects of ER stress on this pathological process. VIDD was induced by volume-controlled mechanical ventilation (MV) for 12 h; Spontaneous breathing (SB, for 12 h) rats were used as controls. The ER stress inhibitor 4-phenylbutyrate (4-PBA), the antioxidant N-acetylcysteine (NAC), and the ER stress inducer tunicamycin (TUN) were given before the onset of MV or SB. Diaphragm function, oxidative stress, and ER stress in the diaphragms were measured at the end of the experiments. ER stress was markedly increased in diaphragms relative to that in SB after 12 h of MV (all < 0.001). Inhibition of ER stress by 4-PBA downregulated the expression levels of proteolysis-related genes in skeletal muscle, including -1 and -1, reduced myofiber atrophy, and improved diaphragm force-generating capacity in rats subjected to MV (all < 0.01). In addition, mitochondrial reactive oxygen species (ROS) production and protein level of 4-HNE (4-hydroxynonenal) were decreased upon 4-PBA treatment in rats during MV (all < 0.01). Interestingly, the 4-PBA treatment also markedly increased the expression of peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α) ( < 0.01), a master regulator for mitochondrial function and a strong antioxidant. However, the antioxidant NAC failed to reduce ER stress in the diaphragm during MV ( 0.05). Finally, ER stress inducer TUN largely compromised diaphragm dysfunction in the absence of oxidative stress (all < 0.01). ER stress is induced by MV and the inhibition of ER stress alleviates oxidative stress in the diaphragm during MV. In addition, ER stress is responsible for diaphragm dysfunction in the absence of oxidative stress. Therefore, the inhibition of ER stress may be another promising therapeutic approach for the treatment of VIDD.
越来越多的证据表明，内质网（ER）应激在骨骼肌质量调节中起关键作用。近年来，呼吸机诱导的膈肌功能障碍（VIDD）受到了广泛关注，因为它对危重症患者的预后有重大影响。目前的证据表明，氧化应激增强是VIDD发生发展的关键，但尚无关于内质网应激对这一病理过程影响的数据。通过容量控制机械通气（MV）12小时诱导VIDD；以自主呼吸（SB，12小时）大鼠作为对照。在内质网应激抑制剂4-苯基丁酸（4-PBA）、抗氧化剂N-乙酰半胱氨酸（NAC）和内质网应激诱导剂衣霉素（TUN）在MV或SB开始前给予。在实验结束时测量膈肌功能、氧化应激和内质网应激。MV 12小时后，膈肌中的内质网应激相对于SB显著增加（均<0.001）。4-PBA对内质网应激的抑制下调了骨骼肌中蛋白水解相关基因的表达水平，包括-1和-1，减少了肌纤维萎缩，并改善了MV大鼠的膈肌力量产生能力（均<0.01）。此外，MV期间4-PBA处理可降低大鼠线粒体活性氧（ROS）产生和4-羟基壬烯醛（4-HNE）蛋白水平（均<0.01）。有趣的是，4-PBA处理还显著增加了过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）的表达（<0.01），PGC-1α是线粒体功能的主要调节因子和强大的抗氧化剂。然而，抗氧化剂NAC未能在MV期间降低膈肌中的内质网应激（>0.05）。最后，内质网应激诱导剂TUN在无氧化应激的情况下极大地加剧了膈肌功能障碍（均<0.01）。MV可诱导内质网应激，抑制内质网应激可减轻MV期间膈肌中的氧化应激。此外，内质网应激在无氧化应激的情况下导致膈肌功能障碍。因此，抑制内质网应激可能是治疗VIDD的另一种有前景的治疗方法。
