Regulation of Neutrophil Responses by p38 MAP Kinase in Acute Lung Injury

描述（由申请人提供）： 在严重感染或休克的情况下，一定比例的患者会发展为急性肺损伤。 损伤（ALI）。其他人，尽管同等或更大的侮辱和类似的风险因素出现 免受综合症的影响。急性肺损伤的一个主要特征是急性肺损伤的快速和大量积累， 中性粒细胞进入肺部中性粒细胞反应程度存在相当大的异质性 存在于正常人群中。因此，在全身性炎症的情况下， 中性粒细胞反应可能导致ALI易感性的变化。许多答复， 目前已知与ALI发病机制相关的中性粒细胞受到调节， p38丝裂原活化蛋白激酶（MAPk）。拟议的研究旨在 表征健康人和正常人中p38 MAPK介导的中性粒细胞反应谱， 疾病，强调中性粒细胞炎症潜力的变异性是疾病的一种机制 ALI的异质性。提出了一种功能性中性粒细胞表型， 基于p38 MAPK活化增加的炎症潜力。具体目标为此 项目是：1）根据炎症反应识别正常中性粒细胞的反应表型。 潜力2)检测中性粒细胞中鉴定的功能表型是否可预测ALI的临床特征。 3)确定中性粒细胞中p38 MAPK调节基因和蛋白表达的模式 不同的炎症潜能。通过同时定量p38 MAPk活化 和一系列p38 MAPK调节的反应，结合基因组分析，中性粒细胞 具有高或低的炎症可能性。趋异性炎症的影响 将通过支气管镜装置在体内测试对肺部炎症的表型， 内毒素对严重ARDS幸存者中性粒细胞的平行研究有望 表现出类似的高炎症潜力模式，而患者？有风险吗谁没有 发展该综合征的患者预期具有低炎性表型。频谱 将描述p38 MAPK调节的蛋白质释放，以及由 p38 MAPK的激活将在人嗜中性粒细胞和小鼠模型中检测。 肺部炎症这些研究将与《公约》中的所有项目协调进行。 项目旨在实现对中性粒细胞信号传导和功能的最广泛分析。

DESCRIPTION (provided by applicant): In the setting of severe infection or shock, a percentage of patients will develop Acute Lung Injury (ALI). Other individuals, despite equal or greater insults and similar risk factors appear protected from the syndrome. A central feature of ALI is rapid and massive accumulation of neutrophils to the lung. Considerable heterogeneity in the magnitude of neutrophil response exists within the normal population. Thus, in the setting of systemic inflammation, variability in the neutrophil response could contribute to variability in predisposition to ALI. Many responses by the neutrophil that have been linked to the pathogenesis of ALI are now known to be regulated by p38 mitogen-activated protein kinase (MAPk). The proposed studies are designed to characterize the spectrum of p38 MAPk-mediated neutrophil response in both health and disease, emphasizing the variability in neutrophil inflammatory potential as a mechanism for heterogeneity in ALI. A functional neutrophil phenotype is proposed that demonstrates a high inflammatory potential based on increased activation of p38 MAPk. Specific Aims for this projects are: 1) Identify response phenotypes in normal neutrophils based on inflammatory potential. 2) Test if functional phenotypes identified in neutrophils predict clinical features of ALI. 3) Define patterns of p38 MAPk-regulated gene and protein expression in neutrophils with divergent inflammatory potential. Through simultaneous quantification of p38 MAPk activation and a series of p38 MAPk-regulated responses, combined with genomic analysis, neutrophils with high or low inflammatory potential will be identified. The effect of divergent inflammatory phenotypes on lung inflammation will be tested in vivo through bronchoscopic installation of endotoxin. Parallel studies of neutrophils from survivors of severe ARDS are expected to demonstrate a similar pattern of high inflammatory potential, while patients ?at risk? who did not develop the syndrome are expected to possess a low inflammatory phenotype. The spectrum of p38 MAPk-regulated protein release will be described, and gene expression mediated by activation of p38 MAPk will be examined in both human neutrophils and in a murine model of pulmonary inflammation. These studies will be coordinated with all of the Projects in the Program to achieve the broadest possible analysis of neutrophil signaling and function.