MOLECULAR MECHANISMS OF LUNG INJURY IN SEPSIS

急性肺损伤是脓毒症和创伤的重要后果， 死亡率仍然很高 急性肺损伤通常发生在 多器官衰竭综合征的一部分的机制 引发和调节脓毒症患者急性肺损伤 更好地定义，以便设计可以 用于保护肺部和全身器官。 这项建议的主要目标是调查细胞和 脓毒症急性肺损伤的分子机制我们将 测试两个主要假设：1）CD 14和一种特异性 空气中的脂多糖结合蛋白（LBP）介导和 增强急性肺结核患者肺部的炎症反应， 肺损伤;和2）旨在中断CD 14依赖性 炎症机制将使局部和全身 肺内感染的炎症后果，并保护 主持人 我们的具体目的是：1）确定CD 14和LBP在肺组织中的作用 急性肺损伤危重患者的炎症; 2） 确定决定净生物活性的关键相互作用 LPS在肺损伤患者的气隙中的含量;以及3）测试 有效的中和sCD 14在空气空间和全身 循环的动物与弥漫性肺损伤引起的非， 肺脓毒症或肺内感染。 这些研究直接遵循正在进行的研究， 目前的融资期，并将提供重要的新信息， 导致急性肺损伤的细胞和分子事件 脓毒症患者中。

Acute lung injury is an important consequence of sepsis and trauma that continues to carry a high mortality. Acute lung injury often occurs as part of the broader syndrome of multiple organ failure. The mechanisms that initiate and modulate acute lung injury in 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. The major goal of this proposal is to investigate the cellular and molecular mechanisms that mediate acute lung injury in sepsis. We will test two major hypotheses: 1) that CD14 and a specific lipopolysaccharide binding protein (LBP) in the airspaces mediate and potentiate the inflammatory response in the lungs of patients with acute lung injury; and 2) that strategies designed to interrupt CD14-dependent inflammatory mechanisms will minimize the local and systemic inflammatory consequences of intrapulmonary infections, and protect the host. Our Specific Aims are: 1) to define the roles of CD14 and LBP in lung inflammation in critically ill patients with acute lung injury; 2) to identify the critical interactions that determine the net bioactivity of LPS in the airspaces of patients with lung injury; and 3) to test the effectiveness of neutralizing sCD14 in the airspaces and the systemic circulation of animals with diffuse lung injury arising either from non- pulmonary sepsis, or intrapulmonary infections. These studies follow directly from studies that are underway in the current funding period, and will provide important new information about the cellular and molecular events that contribute to acute lung injury in patients with sepsis.