Pathogenesis of Oxidative Stress in Chagasic Myocarditis

描述（由申请人提供）：恰格巴氏病心肌病（CCM）是拉丁美洲和墨西哥的一种主要公共卫生威胁，在美国被认为是一种新兴的传染病。来自该疾病不同临床阶段患者的肌内膜活检表明，心肌炎症和纤维化在其发病机制中起重要作用。由于在进行性CCM期间仅检测到少数寄生虫（如果有的话），因此认为其他因素参与激活和/或维持炎症反应。然而，这些因素是未知的。我们已经在实验模型中表明，T。Cruzi消除了与氧化修饰和呼吸链复合物的活性改变、活性氧（ROS）的产生和心肌中的持续氧化损伤相关的线粒体功能障碍。我们的其他研究表明，抗氧化剂治疗可以有效地限制心肌细胞中促炎细胞因子的产生，以及T。克鲁兹在这个项目中，我们将确定1）线粒体ROS和呼吸链缺陷在引起心肌细胞促炎反应和随后的炎症细胞在心脏病心脏中的募集中的关键作用，以及2）线粒体氧化还原诱导的反应在进行性疾病的心功能不全中的生物学意义。我们的中心假设是T. cruzi诱导的线粒体膜和呼吸复合体的损伤导致持续的ROS产生。这些ROS在维持心肌细胞中的氧化应激和引发促炎细胞因子方面至关重要，从而为炎症性心脏中炎性细胞的持续募集提供刺激。完成拟议的项目将提供线粒体ROS在启动和/或维持病理过程（炎症，氧化损伤，纤维化）中的作用的基本理解，这些病理过程导致CCM的心功能障碍。未来的分子和机制研究将确定旨在管理线粒体功能或增强抗氧化防御能力的治疗是否会有效降低CCM的严重程度。

DESCRIPTION (provided by applicant): Chagasic cardiomyopathy (CCM), a major public health threat in Latin America and Mexico, is recognized as an emerging infectious disease in the U.S. Endomyocardial biopsies from patients in different clinical stages of the disease have suggested that myocardial inflammation and fibrosis play an important role in its pathogenesis. Because only a few, if any, parasites are detected during progressive CCM, other factors are believed involved in activation and/or sustaining the inflammatory response. These factors are, however, not known. We have shown in experimental models that infection by T. cruzi elicits mitochondrial dysfunction associated with oxidative modifications and altered activities of the respiratory chain complexes, generation of reactive oxygen species (ROS), and sustained oxidative damage in the myocardium. Our other studies show that antioxidant treatment is effective in limiting production of proinflammatory cytokines in cardiomyocytes, and recruitment of inflammatory cells in murine hearts infected by T. cruzi. In this project, we will determine 1) the pivotal role of mitochondrial ROS and respiratory chain deficiencies in eliciting the proinflammatory response in cardiomyocytes and subsequent recruitment of inflammatory cells in chagasic hearts, and 2) the biological significance of the mitochondrial redox-induced responses in cardiac dysfunction with progressive disease. Our central hypothesis is that T. cruzi-induced injuries of the mitochondrial membranes and respiratory complexes result in sustained ROS generation. These ROS are critical in sustaining oxidative stress and eliciting pro-inflammatory cytokines in cardiomyocytes, and thus provide stimuli for the consistent recruitment of inflammatory cells in chagasic hearts. Completion of the proposed project will provide a basic understanding of the role of mitochondrial ROS in initiating and/or sustaining pathological processes (inflammation, oxidative damage, fibrosis,) that contribute to cardiac dysfunction in CCM. Future molecular and mechanistic studies would determine whether therapies designed to manage the mitochondrial function or to enhance antioxidant defense capacity would effectively reduce severity of CCM.