MECHANICAL VENTILATION AND RESPIRATORY MUSCLES

描述（申请人摘要）：使用机械通气（MV） 在临床上用于维持无法进行 独立维持足够的肺泡通气。可惜 在许多情况下，MV的撤回或断奶可能是困难的。 强有力的证据表明MV诱导的呼吸肌无力有助于 这对断奶的困难有很大的影响。事实上，我们最近 表明MV延长会导致脑萎缩， 显著减少了最大的机械力产生。我们还 已经观察到延长的MV导致氧化损伤（即蛋白质 氧化）到隔膜;这是重要的，因为氧化的蛋白质 成为蛋白酶的目标。这种MV诱导的机制 萎缩和蛋白质氧化是未知的，包括我们的重点 提出的实验。为了确定导致脑卒中的因素， 在长时间MV期间的萎缩，我们将测试以下假设：1a） MV-诱导的脑萎缩是由于合成减少， 肌肉蛋白质以及蛋白质水解率增加; 1b）蛋白质水解是 在延长的MV期间，主要的促炎蛋白损失的贡献者; 2a） 钙蛋白酶、溶酶体和ATP泛素依赖性的活性增加， 蛋白酶共同负责观察到的蛋白质降解， 隔膜从MV动物;和2b）虽然钙蛋白酶，溶酶体， ATP-泛素依赖的蛋白酶都有助于蛋白质的丢失 在MV过程中，ATP-泛素依赖性和钙蛋白酶蛋白水解途径， 占主导地位。为了解决哪些化学途径是导致癌症的原因， 我们将检验MV诱导的蛋白质氧化的假设， 隔膜中的氧化是由几种反应性化学物质引起的 包括次氯酸、酪氨酰自由基和羟基自由基。测试 这些假设，我们将进行体外和体内研究， 动物模型，并利用分子生物学，生物化学， physiology.这些实验将提高我们对这些机制的理解 与MV诱导的脑萎缩相关。我们的长期目标是 实验是为了提供开发临床策略所需的知识 对抗MV对呼吸肌的有害影响。

DESCRIPTION (Applicant's abstract): Mechanical ventilation (MV) is used clinically to sustain ventilation in patients who are incapable of independently maintaining adequate alveolar ventilation. Unfortunately, the withdrawal of MV, or weaning, can be difficult in a large number of cases. Strong evidence exists that MV-induced respiratory muscle weakness contributes significantly to these difficulties in weaning. Indeed, we have recently demonstrated that prolonged MV results in diaphragmatic atrophy and a significant reduction in diaphragmatic maximal force production. Further, we have observed that prolonged MV results in oxidative injury (i.e. protein oxidation) to the diaphragm; this is significant because oxidized proteins become targets for proteases. The mechanisms responsible for this MV-induced atrophy and protein oxidation are unknown and comprise the focus of our proposed experiments. To determine the factors that contribute to diaphragmatic atrophy during prolonged MV, we will test the following hypotheses: 1a) MV-induced diaphragmatic atrophy occurs due to a decrease in synthesis of muscle proteins as well as an increased rate of proteolysis; 1b) proteolysis is the major contributor to diaphragmatic protein loss during prolonged MV; 2a) The increased activity of calpain, lysosomal, and ATP ubiquitin-dependent proteases are collectively responsible for the protein degradation observed in diaphragms from MV animals; and 2b) Although calpain, lysosomal, and ATP-ubiquitin-dependent proteases all contribute to diaphragmatic protein loss during MV, the ATP-ubiquitin-dependent and calpain proteolytic pathways are dominant. To resolve which chemical pathways are responsible for diaphragmatic protein oxidation during MV we will test the hypothesis that MV-induced protein oxidation in the diaphragm is caused by several reactive chemical species including hypochlorous acid, tyrosyl radicals and hydroxyl radicals. To test these postulates, we will perform both in vitro and in vivo studies using an animal model and utilize the tools of molecular biology, biochemistry, and physiology. These experiments will improve our understanding of the mechanisms associated with MV-induced diaphragmatic atrophy. The long-term goal of our experiments is to provide the knowledge required to develop clinical strategies to oppose the deleterious effects of MV on respiratory muscles.