Pathogenesis of Oxidative Stress in Chagasic Myocarditis

描述(申请人提供)：查加西克心肌病(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出现的传染病。来自该疾病不同临床阶段的患者的心内膜心肌活检表明，心肌炎症和纤维化在其发病机制中起着重要作用。由于在进行性CCM期间只检测到少数寄生虫，因此其他因素被认为参与了激活和/或维持炎症反应。然而，这些因素并不为人所知。我们已经在实验模型中表明，克氏毛滴虫感染引起线粒体功能障碍，与呼吸链复合体的氧化修饰和活性改变有关，产生活性氧物种(ROS)，并在心肌中持续氧化损伤。我们的其他研究表明，抗氧化治疗有效地限制了心肌细胞中促炎细胞因子的产生，并限制了感染毛滴虫的小鼠心脏中炎性细胞的募集。在这个项目中，我们将确定1)线粒体ROS和呼吸链缺陷在引发心肌细胞的促炎反应和随后的心脏炎症细胞募集中的关键作用，以及2)线粒体氧化还原诱导的反应在进展性疾病的心功能障碍中的生物学意义。我们的中心假设是，克氏锥虫诱导的线粒体膜和呼吸复合体的损伤会导致持续的ROS产生。这些ROS在维持氧化应激和在心肌细胞中激发促炎细胞因子方面起关键作用，从而为心脏中持续的炎性细胞募集提供刺激。拟议项目的完成将使人们对线粒体ROS在启动和/或维持导致CCM心功能障碍的病理过程(炎症、氧化损伤、纤维化)中的作用有一个基本的了解。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疗法是否能有效降低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.