Macrophage Gene Expression in Acute Lung Inflammation

描述（由申请人提供）：需要更好地定义严重脓毒症患者炎症反应的调节机制，以便设计可用于保护肺部和防止多器官衰竭导致死亡的特异性治疗方法。肺巨噬细胞是一种免疫效应细胞，在内毒素反应中介导嗜中性肺炎症的分子病理生物学。本研究的总体目标是研究PU.1基因表达是否是肺巨噬细胞参与ARDS的关键决定因素。我们假设PU。1通过两种综合机制调节肺巨噬细胞对内毒素的反应：a)诱导toll样受体，可以触发NF-（B激活途径）；B)通过增强炎症基因的产生，如COX-2，有助于细胞因子和趋化因子介导的肺部炎症的发展。我们提出了三个具体目的：1)确定PU.1基因表达或激活状态在内毒素治疗下的变化，2)确定PU.1在内毒素治疗下增加炎症介质产生的机制，以及3)确定PU.1在腹膜脓毒症小鼠模型中对中性粒细胞肺炎症发展的相对贡献。在严重脓毒症的情况下，巨噬细胞分化的信号募集可能代表了一个可再生的内毒素反应性肺巨噬细胞池，这有助于中性粒细胞肺炎症的开始、强度和持续时间。我们的研究旨在探讨PU.1参与巨噬细胞对内毒素反应的基本分子机制，以期为ARDS提供新的治疗方法。

DESCRIPTION (provided by applicant): The mechanisms that regulate inflammatory response in humans with severe sepsis need to be better defined in order to design specific therapies that can be used to protect the lungs and prevent death from multiple organ failure. Pulmonary macrophages are immune-effector cells that mediate the molecular pathobiology of neutrophilic lung inflammation in response to endotoxin. The overall goal of this proposal is to investigate whether PU.1 gene expression is critical determinant of pulmonary macrophage involvement in ARDS. We hypothesize that PU. 1 regulates the response of pulmonary macrophages to endotoxin through two integrated mechanisms: a) induction of Toll-like receptors that can trigger the NF-(B activation pathway and b) through enhancement of inflammatory gene production, such as COX-2, that contributes to the development of cytokine and chemokine mediated lung inflammation. We propose three specific aims: 1) To define changes in PU.1 gene expression or activation state in response to treatment with endotoxin, 2) To determine the mechanisms by which PU.1 increases production of inflammatory mediators in response to treatment with endotoxin, and 3) To identify the relative contribution of PU.1 to the development of neutrophilic lung inflammation in a murine model of peritoneal sepsis. In the setting of severe sepsis, signaled recruitment of differentiation of macrophages may represent a renewable pool of endotoxin responsive pulmonary macrophages that contribute to the initiation, intensity, and duration of neutrophilic lung inflammation. Our studies are designed to investigate the basic molecular mechanism by which PU.1 is involved in the response of macrophages to endotoxin with the hope that this leads to novel treatments for ARDS.