Myocardial Endotoxin Signaling in Surgery

描述（来自申请人摘要的逐字记录）细菌释放 内毒素（脂多糖，LPS）进入循环发生在败血症， 以及重大创伤和手术后。仅脓毒症就影响了50多万人 在美国，每年约有100万患者，其中近一半死亡。LPS触发物 全身炎症反应和多器官功能障碍， 免疫细胞和非骨髓细胞的激活。内毒素血症性心肌 功能障碍是脓毒症发病率和死亡率的重要决定因素; 它和相关的机制也与病理生理学有关， 心脏衰竭和心肺转流。 本提案和其他调查员提供的新资料 表明受体介导的和直接的细胞内运输 LPS可能负责刺激细胞内信号传导 级联反应、细胞功能扰动和基因转录事件 导致脂多糖诱导的细胞损伤这些影响发生相当 快速（30-60分钟），包括心肌收缩力降低， 钙调节、氧消耗、异常线粒体转运和游离 激进生产。这些异常与多发性硬化的发生相一致。 信号通路和LPS转运到细胞内位点，包括 线粒体、高尔基体和收缩器。 本项目使用培养的心肌细胞和离体灌注心脏，将测试 三种假说：1）LPS激活Toll样受体及其相关信号 转导蛋白; 2）膜结合和细胞内转运 的LPS负责信号传导和功能效应;和3）LPS或 LPS激活的信号转导通路导致线粒体功能障碍。 考虑到LPS信号起始机制的潜在多样性和LPS信号的表达， 随后的细胞反应的多效性，定义了最早的 LPS信号传导的机制对于设计特异性和 有效的治疗策略。此外，这些研究的结果是 可能不仅适用于内毒素，也适用于宿主对其他外源性 病原体的产品，并在更广泛的意义上，了解的作用， 刺激各种形式的心肌细胞中的先天性和适应性免疫 损伤

DESCRIPTION (Verbatim from the applicant's abstract) Release of bacterial endotoxin (lipopolysaccharide, LPS) into the circulation occurs in sepsis, as well as after major trauma and surgery. Sepsis alone affects more than 500,000 patients per year in the United States, nearly half of which die. LPS triggers a systemic inflammatory response and multi-organ dysfunction due to cellular activation of both immune and non-myeloid cells. Endotoxemia-induced myocardial dysfunction is an important determinant of morbidity and mortality in sepsis; it and related mechanisms have also been associated with the pathophysiology of heart failure and cardiopulmonary bypass. New information detailed in the present proposal and from other investigators indicates that both receptor mediated and direct intracellular trafficking of LPS are likely to be responsible for stimulating the intracellular signaling cascades, perturbation of cellular functions, and gene transcription events that are responsible for LPS-induced cellular injury. These effects occur quite rapidly (30-60 min) and include decreased myocardial contractility, abnormal calcium regulation, oxygen wastage, abnormal mitochondrial transport, and free radical production. These abnormalities coincide with initiation of multiple signaling pathways and the transport of LPS to intracellular sites including mitochondria, Golgi, and the contractile apparatus. This project using myocytes in culture and isolated perfused hearts, will test three hypotheses: 1) that LPS activates Toll-like receptors and related signal transduction proteins; 2) that membrane association and intracellular transport of LPS are responsible for signaling and functional effects; and 3) that LPS or LPS-activated signal transduction pathways cause mitrochondrial dysfunction. Given the potential diversity of the mechanism of LPS signal initiation and the pleiotropic nature of subsequent cellular responses, defining the earliest mechanisms of LPS signaling is essential to the design of specific and effective treatment strategies. Furthermore, the results from these studies are likely to apply not only endotoxin but also to host responses to other foreign pathogen products, and, in a more general sense, to understanding the role of stimulation of innate and adaptive immunity in various forms of myocardial injury.