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， 术后呼吸道并发症的风险增加，更需要延长机械治疗时间 通风。然而，目前尚不清楚糖尿病是如何导致这些问题的。一种可能的解释是 这种失控的糖尿病改变了呼吸肌功能，降低了呼吸泵的容量。 本提案的目的是审查这一问题。我们的中心假设是，控制不善 糖尿病导致严重的自由基介导的横隔膜功能障碍。我们将在 以下是一组研究。目的研究未控制的糖尿病对横隔膜的影响。 比力产生、肌肉质量变化和横隔膜耐力，检验这一假说 糖尿病引起的横隔膜功能的改变与自由基生成的增加有关。 AIM II研究将询问肌肉(包括细胞)中的一些自由基产生途径 表面NADPH氧化酶)，并确定哪些途径导致自由基增加 糖尿病患者在横隔膜中产生。AIM III研究将确定iNOS是否在 糖尿病中的横隔膜，并将检验iNOS作为自由基上游调节剂的假设 一代。AIM IV研究将检测糖尿病引起的自由基的几个下游靶点 在隔膜中产生，导致隔膜性能降低，包括 收缩蛋白的改变、钙蛋白酶介导的肌肉质量减少和线粒体的改变 三磷酸腺苷发电能力。各种生理、生化、蛋白质组、荧光、药理和 基因技术将被用来检验这些假说。我们的初步数据是第一个 骨骼肌中NADPH氧化酶亚单位蛋白在任何疾病过程中上调的证据， 提示iNOS对大鼠膈肌NADPH氧化酶活性和自由基产生有调节作用。 糖尿病。这些新的数据应该为糖尿病的发病机制提供重要信息。 诱发的横隔膜功能障碍，并发现可提供新的治疗靶点的途径 在这种情况下呼吸肌无力的治疗。

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.