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例患者 在美国最近的研究表明，ALI的死亡率仍然很高， 大于30%。急性肺损伤（ALI）的特征是肺内 肺部中性粒细胞活化然而，即使导致中性粒细胞 激活是众所周知的，其在ALI的背景下的控制机制知之甚少。 我们认为，表型模式的存在决定了中性粒细胞反应的性质 促炎性刺激，从而不仅有助于发展的ALI，但其 也是持久性和持久性。这项工作的目标是确定关键的遗传因素， 以及导致某些个体而非其他个体发生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动脉压升高相关， 炎症，发生急性肺损伤的可能性更大， 急性肺损伤我们还假设这种促炎中性粒细胞表型是 其特征在于促炎细胞因子的产生增加， p38和PI 3 K/Akt激酶、增加的NF-κ B活化和对糖皮质激素的抗性。这 本计划中的四个项目和三个核心将对这一假设进行探索。的 每个项目的第一个具体目标是确定人类高和低炎症表型 中性粒细胞，定义如下：a）PI 3-K、Akt和NF-κ B的活化（Project One）; B的活化 p38（项目二）; c）促炎细胞因子的表达（项目三）;和d）对类固醇诱导的细胞死亡的抗性和细胞因子产生的抑制（项目四）。每个项目的第二个具体目标是确定中性粒细胞中的高和低炎症表型（如第一个具体目标中所定义）是否预测a）给予肺内毒素的人体体内肺部炎症反应的强度，和B）处于ALI风险或患有ALI的患者中肺损伤的严重程度。每个项目的第三个具体目标是确定a）PI 3-K、Akt和NF-κ B激活（项目一）; B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。PPG申请中提出的综合方法不仅可以深入了解引发和导致ALI严重程度的细胞途径，还可以深入了解导致某些个体而非其他个体发生ALI的关键遗传、免疫和环境风险因素。

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.