MOLECULAR MECHANISMS OF LUNG INJURY IN SEPSIS

急性肺损伤是脓毒症和创伤的重要后果， 死亡率仍然居高不下。急性肺损伤通常发生在 这是更广泛的多器官衰竭综合征的一部分。其作用机制 在脓毒症患者中启动和调节急性肺损伤 为了更好地定义，以便设计特定的治疗方法 用来保护肺部和全身器官。 这项提案的主要目标是调查蜂窝和 脓毒症急性肺损伤的分子机制。我们会 检验两个主要假设：1)CD14和一个特定的 空气中的脂多糖结合蛋白(LBP)介导和 增强急性呼吸窘迫综合征患者肺部炎症反应 肺损伤；以及2)旨在阻断CD14依赖的策略 炎症机制将使局部和全身炎症最小化。 肺内感染的炎症后果，并保护 主持人。 我们的具体目标是：1)明确CD14和LBP在肺中的作用 急性肺损伤危重患者的炎症反应；2) 确定决定净生物活性的关键相互作用 肺损伤患者空气中内毒素的含量；以及3)检测 中和空域和全身sCD14的有效性 弥漫性肺损伤动物的循环 肺脓毒症，或肺内感染。 这些研究直接来自正在进行的研究 目前的资助期，并将提供有关 导致急性肺损伤的细胞和分子事件 在脓毒症患者身上。

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.