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

急性肺损伤中 p38 MAP 激酶对中性粒细胞反应的调节

• 批准号: 6553927
• 负责人: JERRY A NICK
• 金额: $ 23.74万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6553927
• 关键词: adult respiratory distress syndrome; clinical research; disease /disorder proneness /risk; endotoxins; enzyme activity; gene expression; genetic susceptibility; human subject; immunogenetics; inflammation; laboratory mouse; mitogen activated protein kinase; neutrophil; phenotype; protein biosynthesis

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.

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(ALI)。其他人，尽管有同等或更大的侮辱和类似的风险因素出现 保护自己免受综合症的侵袭。ALI的一个中心特征是快速而大量的积累 中性粒细胞进入肺部。中性粒细胞反应的大小有相当大的异质性 存在于正常人群中。因此，在全身性炎症的背景下， 中性粒细胞反应可能导致ALI易感性的变化。许多回复来自 目前已知与ALI发病相关的中性粒细胞受到调节。 通过p38丝裂原活化蛋白激酶(MAPK)表达。拟议的研究旨在 健康人群和健康人群p38MAPK介导的中性粒细胞反应谱特征 疾病，强调中性粒细胞炎症潜能的可变性是一种 ALI中的异质性。提出了一种功能性中性粒细胞表型，该表型显示出高 基于p38 MAPK活化增加的炎症潜能。这方面的具体目标 项目包括：1)根据炎症反应确定正常中性粒细胞的反应表型 潜力。2)检测中性粒细胞功能表型是否能预测ALI的临床特征。 3)确定p38 MAPK调节的基因和蛋白在中性粒细胞中的表达模式 发散的炎性潜势。通过同时量化p38 MAPK的激活 和一系列p38 MAPK调节的反应，结合基因组分析，中性粒细胞 具有高或低炎症潜在性的将被识别。发散性炎症的作用 将通过支气管镜安装在体内测试肺部炎症的表型 内毒素。对严重ARDS幸存者的中性粒细胞的平行研究有望 表现出类似的高炎症潜在性模式，而患者？处于危险之中？谁没有呢？ 发展为该综合征的患者预计具有低炎性表型。光谱 将描述p38 MAPK调节的蛋白释放，并通过 P38MAPK的激活将在人中性粒细胞和小鼠模型中进行检测。 肺部发炎。这些研究将与 程序以实现对中性粒细胞信号和功能的最广泛的分析。