Ventilator-induced diaphragm dysfunction

描述(由申请人提供)：最近在大鼠身上的研究表明，与隔膜不活动相关的长时间(即12小时)机械通气(MV)导致隔膜作用力显著减少。如果这种疾病也发生在接受机械通气的人身上，这可以解释一些患者停止机械通气的困难(即脱机困难)，以及一些无法脱离机械通气的患者。大鼠研究表明，(A)氧化应激，(B)蛋白分解增加，(C)暴露于长时间机械通气(即PMV)的大鼠膈肌纤维发生萎缩。我们对血液循环完整的PMV脑死亡器官捐赠者的初步观察表明，这种疾病也可能发生在人类身上。在拟议的研究中，我们将进行配对病例对照研究，以回答以下问题：(1)接触PMV的人是否也会发生类似的疾病？以及(2)PMV在人体横隔膜中产生的是什么病理？我们将脑死亡器官捐赠者定义为具有以下特征的患者：(A)接受MV治疗12小时但72小时；(B)在MV停止前立即接受横隔膜活检；以及(C)无感染。我们将匹配对照定义为患有孤立性肺结节(SPN)的患者，该患者(A)相同年龄(5岁)；(B)相同性别；(C)术中横隔活检前3小时接受神经肌肉阻滞剂；(D)SPN病理显示良性疾病；(E)无感染。我们以前已经证明，对照没有表现出横隔膜的病理。因此，我们将通过比较每个配对的病例和对照来检验我们的每个假设。要检验的具体假设是，与对照组相比，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的单一渗透性纤维的比力和力产生的钙敏感性降低；(C)由于calain活性和泛素-蛋白质结合上调而导致蛋白质分解增加；(D)肌纤维萎缩(约25%-30%)和(E)计算的最大横隔力产生显著减少。对于这些变化中的每一种，我们详细的蛋白质组、基因组、生理和组织学研究将提供一种机械解释。总之，这些研究可能会定义一种新的横隔膜疾病，这种疾病相当普遍，导致我们患者的生活质量严重下降，而且对于我们有限的医疗保健资金来说，也是非常昂贵的。此外，这些研究可能直接导致治疗这种新发现的但相对常见的横隔肌疾病。

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.