Heterogeneous Neutrophil Responses in Acute Lung Injury

描述(由申请人提供)： 急性肺损伤(ALI)是一个主要的临床问题，每年影响超过50,000名患者 在美国。最近的研究表明，ALI的死亡率总体上仍然很高。 超过30%的。急性肺损伤(ALI)的特点是 肺部的中性粒细胞被激活。然而，即使通向中性粒细胞的途径 激活是众所周知的，但它们在ALI背景下的控制机制却知之甚少。 我们认为存在决定中性粒细胞反应性质的表型模式。 促炎症刺激，从而不仅有助于ALI的发展，而且有助于其 严肃性和毅力也是如此。拟议工作的目标是定义关键的基因 以及导致某些人而不是其他人发生ALI的细胞风险因素。我们的假设是 促炎性中性粒细胞表型与肺功能增加相关 炎症，更有可能发展为急性肺损伤，以及更糟糕的结果 急性肺损伤。我们还假设这种促炎性中性粒细胞表型是 其特征是促炎症细胞因子的产生增加，增强了 P38和PI3K/Akt激酶，增加了核因子-kB的活性，并对糖皮质激素产生了抵抗。这 假设将通过本计划中的四个项目和三个核心进行探索。这个 每个项目的第一个具体目标是确定人类的高和低炎症表型 中性粒细胞，如a)激活PI3-K、Akt和核因子-kB(方案一)；b)激活 P38(项目二)；c)致炎细胞因子的表达(项目三)；以及d)抵抗类固醇诱导的细胞死亡和抑制细胞因子的产生(项目四)。每个项目的第二个特定目标是确定第一个特定目标中定义的中性粒细胞的高炎症表型和低炎症表型是否可以预测a)将内毒素注入肺部的人体内肺部炎症反应的强度，以及b)有ALI风险或合并ALI的患者的肺损伤的严重程度。每个项目的第三个具体目标是确定a)PI3-K、Akt和NF-kB激活(项目一)；b)p38激活(项目二)；c)促炎细胞因子产生(项目三)；和d)糖皮质激素抵抗(项目四)导致促炎中性粒细胞表型的机制。这个PPG应用程序中提出的集成方法不仅可以洞察引发和促成ALI严重程度的细胞通路，还可以洞察导致某些人而不是其他人发生ALI的关键遗传、免疫学和环境风险因素。

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a major clinical problem, affecting more than 50,000 patients per year in the United States. Recent studies have shown that the mortality of ALI remains high, generally being greater than 30%. Acute lung injury (ALI) is characterized by the accumulation of activated neutrophils in the lungs. However, even though pathways leading to neutrophil activation are well known, their control mechanisms in the context of ALI are poorly understood. We propose that phenotypic patterns exist that determine the nature of the neutrophil response to proinflammatory stimuli, thereby contributing not only to the development of ALI, but to its severity and persistence as well. The goal of the proposed work is to define the critical genetic and cellular risk factors that lead to ALI in certain individuals and not others. Our hypothesis is that a proinflammatory neutrophil phenotype is associated with increased pulmonary inflammation, a greater likelihood of developing acute lung injury, and worse outcome from acute lung injury. We also hypothesize that this proinflammatory neutrophil phenotype is characterized by increased production of proinflammatory cytokines, enhanced activation of p38 and PI3K/Akt kinases, increased NF-kB activation, and resistance to glucocorticoids. This hypothesis will be explored by the four Projects and three Cores included in this Program. The first Specific Aim of each Project is to define high and low inflammatory phenotypes in human neutrophils, as defined by a) activation of PI3-K, Akt, and NF-kB (Project One); b) activation of p38 (Project Two); c) expression of proinflammatory cytokines (Project Three); and d) resistance to steroid induced cell death and inhibition of cytokine production (Project Four). The second Specific Aim of each project is to determine if high and low inflammatory phenotypes among neutrophils, as defined in the first Specific Aim, predict a) the intensity of in vivo pulmonary inflammatory responses in humans given endotoxin into the lungs, and b) the severity of lung injury in patients at risk for or with ALI. The third Specific Aim of each project is to determine the mechanisms by which a) PI3-K, Akt, and NF-kB activation (Project One); b) p38 activation (Project Two); c) proinflammatory cytokine production (Project Three); and d) glucocorticoid resistance (Project Four) lead to proinflammatory neutrophil phenotypes. The integrated approach proposed in this PPG application will provide insight not only into cellular pathways that initiate and contribute to the severity of ALI, but also into the critical genetic, immunologic, and environmental risk factors that lead to ALI in certain individuals, but not others.