Molecular Mechanisms of Lung Inflammation

描述（由申请人提供）：脓毒症综合征通常是全身性的， 肺部局部感染的结果。启动的机制 并调节脓毒症患者肺部的炎症反应， 更好地定义，以便设计可用于 保护肺部和全身器官。肺部的细菌及其产物 和体循环启动脓毒症综合征，部分是通过特定的 组织中白细胞和其他细胞表面的识别分子 和循环。我们正在进行的研究的主要目标是了解如何 通过特定模式识别受体启动的先天免疫机制 在细胞表面引发和延续急性肺损伤和脓毒症 综合征 我们的具体目标是：1）确定介导宿主反应的途径， 正常人和ARDS患者肺中的细菌产物; 2） 定义肺中表达主要模式识别的细胞 革兰氏阴性和革兰氏阳性细菌产物的受体，以及 在急性细菌性肺炎中发生的表达变化; 3）确定 白细胞和非髓细胞上模式识别受体的作用 (CD14 TLR 2、TLR 4和信号蛋白MyD 88）在革兰氏阴性菌清除中的作用 阳性和革兰氏阴性细菌从肺部，使用小鼠与靶向 基因缺失; 4）确定阻断CD 14、TLR 4、TLR 2和/或MD 2 保护兔免受局部肺的有害全身效应 感染. 这些持续研究的结果将提供重要的新信息 关于控制对细菌产物的反应的机制， 肺，以及抑制特定模式识别途径的后果 在肺部和体循环中。

DESCRIPTION (provided by applicant): The sepsis syndrome is often a systemic consequence of localized infections in the lungs. The mechanisms that initiate and modulate inflammatory responses in the lungs of humans with sepsis need to be better defined in order to design specific therapies that can be used to protect the lungs and systemic organs. Bacteria and their products in the lungs and systemic circulation initiate the sepsis syndrome, in part through specific recognition molecules on the surface of leukocytes and other cells in tissue and the circulation. The major goal of our ongoing studies is to understand how innate immune mechanisms initiated via specific pattern recognition receptors on the cell surface initiate and perpetuate acute lung injury and sepsis syndrome. Our Specific Aims are: 1) to define the pathways that mediate host responses to bacterial products in the lungs of normal humans and patients with ARDS; 2) to define the cells in the lungs that express the major pattern recognition receptors for gram negative and gram positive bacterial products, and the changes in expression that occur in acute bacterial pneumonia; 3) to determine the role of pattern recognition receptors on leukocytes and non-myeloid cells (CD14, TLR2, TLR4 and the signaling protein MyD88) in the clearance of gram positive and gram negative bacteria from the lungs, using mice with targeted gene deletions; 4) to determine whether blockade of CD14, TLR4, TLR2 and/or MD2 protects rabbits from the deleterious systemic effects of localized lung infections. The results of these continuing studies will provide important new information about the mechanisms that control the response to bacterial products in the lungs, and the consequences of inhibiting specific pattern recognition pathways in the lungs and the systemic circulation.