Relationship between Autophagy and Ventilator-induced Diaphragmatic Dysfunction
Relationship between Autophagy and Ventilator-induced Diaphragmatic Dysfunction
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DOI：
10.1097/aln.0000000000000656
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发表时间：
2015-06-01
期刊：
影响因子：
8.8
通讯作者：
Petrof, Basil J.
中科院分区：
文献类型：
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作者：
Azuelos, Ilan;Jung, Boris;Petrof, Basil J.
背景资料：机械通气（MV）与膈肌萎缩和无力有关，这种情况称为呼吸机诱导的膈肌功能障碍（VIDD）。自噬是一种溶酶体介导的蛋白水解过程，可被氧化应激激活，有可能减轻或加重VIDD。本研究的主要目的是（1）确定MV对自噬的影响，在隔膜和（2）评估抗氧化剂治疗对自噬诱导和MV诱导的mammatic weakness.Methods的影响：小鼠被分配到控制（CTRL），MV（6小时），MV + N-乙酰半胱氨酸，MV +雷帕霉素，和延长（48小时）禁食组。通过定量（1）透射电子显微镜下的自噬囊泡，（2）自噬相关基因的信使RNA水平，和（3）自噬体标记蛋白LC 3B-II，在有和没有秋水仙碱给药的情况下，计算相对自噬体形成和降解的指数，来监测自噬。力生产由小鼠隔膜测定离体vivo.Results：隔膜表现出2.2倍（95%CI，1.8至2.5）增加自噬囊泡可视化通过透射电子显微镜相对于CTRL后6小时的MV（n = 5每组）。MV期间，仅膈肌中的自噬体形成指数增加（1.5倍; 95% CI，1.3至1.8;每组n = 8），而长期禁食诱导膈肌（2.5倍; 95% CI，2.2至2.8）和肢体肌肉（4.1倍; 95% CI，1.8至6.5）中的自噬体形成。抗氧化剂N-乙酰半胱氨酸进一步增强了MV期间膈肌中的自噬体形成（1.4倍; 95% CI，1.2至1.5;每组n = 8），并防止MV诱导的肌无力。自噬诱导剂雷帕霉素的治疗也在很大程度上防止了与MV相关的肌力损失（n = 6/组）。结论：在该VIDD模型中，自噬由MV诱导，但不引起肌力减弱。作者提出，自噬可能是一种有益的适应性反应，可用于治疗VIDD。
Background: Mechanical ventilation (MV) is associated with atrophy and weakness of the diaphragm muscle, a condition termed ventilator-induced diaphragmatic dysfunction (VIDD). Autophagy is a lysosomally mediated proteolytic process that can be activated by oxidative stress, which has the potential to either mitigate or exacerbate VIDD. The primary goals of this study were to (1) determine the effects of MV on autophagy in the diaphragm and (2) evaluate the impact of antioxidant therapy on autophagy induction and MV-induced diaphragmatic weakness.Methods: Mice were assigned to control (CTRL), MV (for 6 h), MV + N-acetylcysteine, MV + rapamycin, and prolonged (48 h) fasting groups. Autophagy was monitored by quantifying (1) autophagic vesicles by transmission electron microscopy, (2) messenger RNA levels of autophagy-related genes, and (3) the autophagosome marker protein LC3B-II, with and without administration of colchicine to calculate the indices of relative autophagosome formation and degradation. Force production by mouse diaphragms was determined ex vivo.Results: Diaphragms exhibited a 2.2-fold (95% CI, 1.8 to 2.5) increase in autophagic vesicles visualized by transmission electron microscopy relative to CTRL after 6 h of MV (n = 5 per group). The autophagosome formation index increased in the diaphragm alone (1.5-fold; 95% CI, 1.3 to 1.8; n = 8 per group) during MV, whereas prolonged fasting induced autophagosome formation in both the diaphragm (2.5-fold; 95% CI, 2.2 to 2.8) and the limb muscle (4.1-fold; 95% CI, 1.8 to 6.5). The antioxidant N-acetylcysteine further augmented the autophagosome formation in the diaphragm during MV (1.4-fold; 95% CI, 1.2 to 1.5; n = 8 per group) and prevented MV-induced diaphragmatic weakness. Treatment with the autophagy-inducing agent rapamycin also largely prevented the diaphragmatic force loss associated with MV (n = 6 per group).Conclusions: In this model of VIDD, autophagy is induced by MV but is not responsible for diaphragmatic weakness. The authors propose that autophagy may instead be a beneficial adaptive response that can potentially be exploited for therapy of VIDD.