Oxidant Mediated Diaphragm Dysfunction in Diabetes

最近的研究表明，糖尿病与呼吸衰竭的发生率增加有关， 术后呼吸系统并发症的风险增加，更需要长时间的机械通气。 通风.然而，尚不清楚糖尿病如何产生这些问题。一个可能的解释是 不受控制的糖尿病会改变呼吸肌功能，降低呼吸泵的能力。 本提案的目的是审查这一问题。我们的核心假设是， 糖尿病诱发严重的自由基介导的横膈膜功能障碍。我们将在下面的文章中检验这一假设： 根据研究组。目的：研究未控制的糖尿病对膈肌的影响 比力的产生，肌肉质量的变化和膈肌耐力，检验假设 糖尿病引起的横隔膜性能的改变与自由基产生的增加有关。 Aim II研究将探究肌肉（包括细胞）中的许多自由基产生途径 表面NADPH氧化酶），并确定哪些途径负责增加自由基 在糖尿病的横膈膜中产生。目的III研究将确定iNOS是否在 隔膜在糖尿病，并将测试的假设，即iNOS作为一个上游调制器的自由基 一代目的IV研究糖尿病诱导的自由基的几个下游靶点 隔膜中产生的导致隔膜性能降低的物质，包括 收缩蛋白改变，钙蛋白酶介导的肌肉质量减少，以及线粒体 ATP生成能力多种生理学、生物化学、蛋白质组学、荧光、药理学和生物化学的研究， 将利用遗传技术来检验这些假设。我们的初步数据代表了 证实在任何疾病过程中骨骼肌中NADPH氧化酶亚单位蛋白的上调， 并表明iNOS调节NADPH氧化酶活性和自由基的产生在膈肌中， 糖尿病这些新的数据应该提供关于糖尿病发病机制的重要信息 诱导的膈肌功能障碍，并揭示了可能提供新的治疗靶点的途径， 呼吸肌无力的治疗方法

Recent studies indicate that diabetes is associated with an increased incidence of respiratory failure, a heightened risk of postoperative respiratory complications, and a greater need for prolonged mechanical ventilation. However, it is not known how diabetes produces these problems. One potential explanation is that uncontrolled diabetes alters respiratory muscle function, reducing the capacity of the respiratory pump. The purpose of the present proposal is to examine this issue. Our central hypothesis is that poorly controlled diabetes induces severe free radical mediated diaphragm dysfunction. We will test this hypothesis in the following groups of studies. Aim I studies will characterize the effects of uncontrolled diabetes on diaphragm specific force generation, changes in muscle mass, and diaphragm endurance, testing the hypothesis diabetes induced alterations in diaphragm performance are related to increases in free radical generation. Aim II studies will interrogate a number of free radical generating pathways in muscle (including the cell surface NADPH oxidase) and determine which pathways are responsible for increased free radical generation in the diaphragm in diabetes. Aim III studies will determine if iNOS is upregulated in the diaphragm in diabetes, and will test the hypothesis that iNOS acts as an upstream modulator of free radical generation. Aim IV studies will examine several downstream targets of diabetes induced free radical generation in the diaphragm that are responsible for reductions in diaphragm performance, including contractile protein alterations, calpain mediated reductions in muscle mass, and alterations in mitochondrial ATP generating capacity. A variety of physiologic, biochemical, proteomic, fluorogenic, pharmacologic and genetic techniques will be used to test these hypotheses. Our preliminary data represent the first demonstration of upregulation of NADPH oxidase subunit proteins in skeletal muscle in any disease process, and suggest that iNOS regulates NADPH oxidase activity and free radical generation in the diaphragm in diabetes. These new data should provide important information regarding the pathogenesis of diabetes induced diaphragm dysfunction, and uncover pathways which could provide novel therapeutic targets for treatment of respiratory muscle weakness in this condition.