Ventilator-induced diaphragm dysfunction

描述（由申请人提供）：最近在大鼠中的研究表明，>12小时）与隔膜不活动相关的机械通气（MV）会导致隔膜力产生显着下降。如果这种疾病也发生在MV患者中，则可以解释某些患者难以停止MV（即，难以脱机）以及一些不能从MV中脱机的患者。大鼠研究表明，在暴露于延长的MV的大鼠的膈肌肌纤维中发生（a）氧化应激、（B）增加的蛋白水解和（c）萎缩的组合（即，PMV）。我们对PMV脑死亡器官捐献者的初步观察表明，这种疾病也可能发生在人类身上。在本研究中，我们将进行配对病例对照研究，以回答以下问题：（1）暴露于PMV的人类是否会发生类似的疾病？（2）PMV在人膈肌中产生了什么样的病理变化？我们将病例定义为具有以下属性的脑死亡器官捐献者：（a）MV>12小时但<72小时;（B）在MV停止前立即进行膈肌活检;（c）无感染。我们将匹配的对照定义为患有孤立性肺结节（SPN）的患者，其（a）相同的年龄〜 5岁;（B）相同的性别;（c）在术中膈肌活检前<3小时接受神经肌肉阻滞剂;（d）SPN的病理学显示良性疾病;以及（e）没有感染。我们以前已经表明，对照组没有表现出膈肌病变。因此，我们将通过比较每个配对的病例和对照来测试我们的每个假设。待检验的具体假设是，与对照相比，病例显示：（a）氧化应激表现为蛋白质羰基化增加和蛋白质酪氨酸硝化增加;（B）肌球蛋白重链和肌钙蛋白特征性单透性纤维中的比力降低和力产生的钙敏感性降低;（c）由于钙蛋白酶活性和泛素-蛋白结合的上调而增加的蛋白水解;（d）肌纤维萎缩（约25-30%）和（e）计算的最大横膈膜力产生显著降低。对于这些变化中的每一个，我们详细的蛋白质组学，基因组学，生理学和组织学研究将提供一个机制的解释。总之，这些研究可能会定义一种新的膈肌疾病，这种疾病非常普遍，会导致患者生活质量严重下降，并且对于我们有限的医疗保健资金来说也非常昂贵。此外，这些研究可能直接导致这种新认识的但相对常见的膈肌疾病的治疗。

DESCRIPTION (provided by applicant): Recent studies in rats demonstrate that prolonged (i.e., >12 hours) mechanical ventilation (MV) associated with diaphragm inactivity elicit marked decreases in diaphragm force generation. If this disorder also occurs in humans on MV, it could explain the difficulty in discontinuing MV in some patients (i.e., difficulty in weaning) as well as for some patients who can not be weaned from MV. The rat studies indicate that a combination of (a) oxidative stress, (b) increased proteolysis, and (c) atrophy occur in diaphragm myofibers of rats exposed to prolonged MV (i.e., PMV). Our preliminary observations on PMV brain-dead organ donors with an intact circulation suggest that this disorder may also occur in humans. In the proposed research, we will carry out a matched pair case control study to answer the following questions: (1) Does a similar disorder occur in humans exposed to PMV? and (2) What pathology is produced by PMV in the human diaphragm? We define a case as a brain dead organ donor who has the following attributes: (a) on MV for >12 hours but <72 hours; (b) undergoes a diaphragm biopsy immediately before cessation of MV; and (c) absence of infection. We define a matched control as a patient with a solitary pulmonary nodule (SPN) that is (a) the same age ¿5 years; (b) same gender; (c) receives neuromuscular blocking agents <3 hours before intra- operative diaphragm biopsy; (d) pathology on SPN shows benign disease; and (e) absence of infection. We have previously shown that controls exhibit no diaphragm pathology. Therefore, we will test each of our hypotheses by comparing cases and controls of each matched pair. The specific hypotheses to be tested are that in comparison to controls, cases show: (a) oxidative stress manifest by increased protein carbonylation and increased protein tyrosine nitration; (b) decreased specific force and decreased calcium sensitivity of force generation in myosin heavy chain and troponin characterized single permeabilzed fibers; (c) increased proteolysis due to an up-regulation of calpain activity and ubiquitin-protein conjugation; (d) myofiber atrophy (approximately 25-30%) and (e) marked decreases in computed maximum diaphragm force generation. For each of these changes, our detailed proteomic, genomic, physiological and histological studies will provide a mechanistic interpretation. In conclusion, these studies may define a new diaphragm disorder that is quite prevalent, causes severely decreased quality of life for our patients, and also is very costly for our limited health care funds. Moreover, these studies may directly lead to therapy for this newly recognized but relatively common disease of diaphragm muscle.