Angiotensin 1-7 protects against ventilator-induced diaphragm dysfunction.
Angiotensin 1-7 protects against ventilator-induced diaphragm dysfunction.
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DOI：
10.1111/cts.13015
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Powers SK
中科院分区：
文献类型：
--
作者：
Yoshihara T;Deminice R;Hyatt HW;Ozdemir M;Nguyen BL;Powers SK
机械通气（MV）是一种挽救生命的仪器，用于为重症患者和接受手术的患者提供呼吸支持。不幸的是，MV延长的非预期后果是由于呼吸肌萎缩和收缩功能障碍导致吸气无力;这种综合征被标记为呼吸机诱导的膈肌功能障碍（VIDD）。VIDD在临床上很重要，因为肌无力是导致患者脱离MV问题的重要因素。VIDD发病机制的研究表明，氧化应激是VIDD的快速发展所必需的，因为隔膜纤维中的氧化还原紊乱促进了加速的蛋白质水解。目前，没有标准的治疗方法来预防VIDD，因此，制定一项战略来避免VIDD至关重要。根据表明膈肌纤维中肾素-血管紧张素系统（RAS）经典轴的激活促进氧化应激和VIDD的证据，我们假设通过血管紧张素1 - 7（Ang 1 - 7）激活非经典RAS信号通路将预防VIDD。使用已建立的MV延长的动物模型，我们的结果揭示了Ang 1 - 7的输注保护隔膜免受MV诱导的收缩功能障碍和快肌纤维和慢肌纤维中的纤维萎缩。此外，Ang 1 - 7保护隔膜纤维免受MV诱导的线粒体损伤、氧化应激和蛋白酶活化。总的来说，这些结果表明，Ang 1 - 7治疗可预防VIDD，部分原因是氧化应激和蛋白酶活化减少。这些重要的发现提供了有力的证据，证明Ang 1 - 7具有通过预防MV诱导的收缩功能障碍和慢肌和快肌纤维萎缩来预防VIDD的治疗潜力。
Mechanical ventilation (MV) is a life‐saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator‐induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin‐angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1‐7 (Ang1‐7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1‐7 protects the diaphragm against MV‐induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1‐7 shielded diaphragm fibers against MV‐induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1‐7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1‐7 has the therapeutic potential to protect against VIDD by preventing MV‐induced contractile dysfunction and atrophy of both slow and fast muscle fibers.
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