Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans
Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans
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DOI：
10.1056/nejmoa070447
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发表时间：
2008-03-27
影响因子：
158.5
通讯作者：
Shrager, Joseph B.
中科院分区：
文献类型：
--
作者：
Levine, Sanford;Nguyen, Taitan;Shrager, Joseph B.
背景资料：膈肌完全不活动和机械通气（超过18小时）的组合会诱发动物肌纤维的废用性萎缩。我们假设，同样可能也发生在人类diaphragm.Methods：我们获得了活检标本从肋膈的14脑死亡的器官捐赠者器官收获前（病例），并将其与术中活检标本从横膈膜的8例患者进行手术，无论是良性病变或局部肺癌（对照组）。病例受试者的睡眠不活跃，并接受了18至69小时的机械通气;在对照受试者中，睡眠不活跃和机械通气仅限于2至3小时。我们对这些标本进行了组织学、生物化学和基因表达研究。与来自对照组的活检标本相比，来自病例受试者的标本显示慢缩和快缩纤维的横截面积减少了57%，（P=0.001）和53%（P=0.01），分别降低谷胱甘肽浓度23%（P=0.01），活性caspase-3表达增加100%（P=0.05），atrogin-1信使RNA（mRNA）转录物与MBD 4的比率高200（管家基因）（P=0.002），MuRF-1 mRNA转录比MBD 4高590%（P=0.001）。结论：18至69小时的完全运动不活动和机械通气的组合导致人膈肌肌纤维的显著萎缩。这些发现与不活动期间增加的淀粉样蛋白水解一致。
Background: The combination of complete diaphragm inactivity and mechanical ventilation (for more than 18 hours) elicits disuse atrophy of myofibers in animals. We hypothesized that the same may also occur in the human diaphragm.Methods: We obtained biopsy specimens from the costal diaphragms of 14 brain-dead organ donors before organ harvest (case subjects) and compared them with intraoperative biopsy specimens from the diaphragms of 8 patients who were undergoing surgery for either benign lesions or localized lung cancer (control subjects). Case subjects had diaphragmatic inactivity and underwent mechanical ventilation for 18 to 69 hours; among control subjects diaphragmatic inactivity and mechanical ventilation were limited to 2 to 3 hours. We carried out histologic, biochemical, and gene-expression studies on these specimens.Results: As compared with diaphragm-biopsy specimens from controls, specimens from case subjects showed decreased cross-sectional areas of slow-twitch and fast-twitch fibers of 57% (P=0.001) and 53% (P=0.01), respectively, decreased glutathione concentration of 23% (P=0.01), increased active caspase-3 expression of 100% (P=0.05), a 200% higher ratio of atrogin-1 messenger RNA (mRNA) transcripts to MBD4 (a housekeeping gene) (P=0.002), and a 590% higher ratio of MuRF-1 mRNA transcripts to MBD4 (P=0.001).Conclusions: The combination of 18 to 69 hours of complete diaphragmatic inactivity and mechanical ventilation results in marked atrophy of human diaphragm myofibers. These findings are consistent with increased diaphragmatic proteolysis during inactivity.