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.
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