Cardiac Depression in Gram-Positive Sepsis--Role of TLR2

描述(申请人提供)：引起的全身炎症反应 革兰氏阳性菌与相当大的发病率和 死亡率可归因于顽固性低血压、心功能障碍和 多器官衰竭。尽管TNF-a、IL-1b具有潜在的重要作用 而NO可能在人类感染性休克的心脏失代偿中起作用， 关于细菌病原体诱导的机制(S)，人们知之甚少 他们在心里的表情。对人类社会的认识有了重大进展 革兰氏阳性细菌信号转导的早期事件已被确认 Toll样受体(TLRs)。最近的研究表明，TLR2可能是一种 与革兰氏阳性细菌及其细胞结合的模式识别受体 墙构件。此外，TLR2是一种有效的信号分子， 激活核因子-kB，导致细胞因子的产生。的长期目标 这项研究的首创性不仅仅是为了描绘分子发病机制 革兰氏阳性感染性休克，但也制定策略，以防止或 减轻败血症对心脏的不良影响。为此， 此应用程序的直接特定目标将是描述角色 TLR2在心功能不全发病机制中的作用 革兰氏阳性败血症休克。我们将检验两个密切相关的假设： 首先，通过TLR-2的信号至少部分地负责诱导 促炎症介质与术后心肌炎症的关系 感染革兰氏阳性菌金黄色葡萄球菌；第二，TLR2 至少在一定程度上对金黄色葡萄球菌的发展负责 左心室收缩功能障碍。这些假设将在 三个具体目标。具体目标1将确定TLR2是否介导 心脏中革兰氏阳性细菌引起的炎症反应。特定的 目标2将确定TLR2是否介导了以下心脏反应 感染金黄色葡萄球菌。具体目标3将决定是否 旨在阻断TLR2信号的免疫治疗干预 预防和/或改善革兰氏阳性脓毒症患者左心功能不全 令人震惊。这些研究将提供有关以下方面的明确的新信息 革兰氏阳性脓毒症的致病机制 心脏的功能和结构。

DESCRIPTION (provided by applicant): The systemic inflammatory response induced by gram-positive bacteria is associated with considerable morbidity and mortality attributable to refractory hypotension, cardiac dysfunction and multiorgan failure. Despite the potentially important role that TNF-a, lL-1b and NO may play in producing cardiac decompensation in human septic shock, little is known with regard to mechanism(s) by which bacterial pathogens induce their expression in the heart. A major advance in the understanding of the early events in gram-positive bacterial signaling has been the identification of Toll-like receptors (TLRs). Recent studies suggest that TLR2 may be a pattern recognition receptor that binds gram-positive bacteria and their cell wall components. In addition, TLR2 is an effective signaling molecule that activates NF-kB, leading to cytokine production. The long-term objectives of this research initiative are not only to delineate the molecular pathogenesis of gram-positive septic shock, but also to develop strategies to prevent or attenuate the untoward effects of sepsis in the heart. Toward this end, the immediate specific objective of this application will be to delineate the role of TLR2 in the pathogenesis of myocardial dysfunction associated with gram-positive septic shock. Two closely interrelated hypotheses will be tested: first, signaling via TLR-2 is responsible, at least in part, for the induction of proinflammatory mediators associated with myocardial inflammation following infection with the gram-positive bacterium Staphylococcus aureus; second, TLR2 is responsible, at least in part, for the development of or S. aureus-induced left ventricular contractile dysfunction. These hypotheses will be tested in three Specific Aims. Specific Aim 1 will determine whether TLR2 mediates the inflammatory response induced by gram-positive bacteria in the heart. Specific Aim 2 will determine whether TLR2 mediates the cardiac response following infection with S. aureus. Specific Aim 3 will determine whether immunotherapeutic interventions designed to interdict signaling via TLR2 prevent and/or modify left ventricular dysfunction in gram-positive septic shock. These studies will provide definitive new information with respect to the mechanisms responsible for the deleterious effects of gram-positive sepsis on cardiac function and structure.