Heterogeneous Neutrophil Responses in Acute Lung Injury

急性肺损伤中的异质中性粒细胞反应

• 批准号: 7095868
• 负责人: Charles anthony Dinarello
• 金额: $ 155.92万
• 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: 2002-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095868
• 关键词: adult respiratory distress syndrome; clinical research; human subject; neutrophil

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.

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 的死亡率仍然很高，一般来说 大于30%。急性肺损伤（ALI）的特点是积累 肺部中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。 我们认为表型模式的存在决定了中性粒细胞反应的性质 促炎症刺激，从而不仅导致 ALI 的发展，而且还导致其 严重性和持久性也是如此。拟议工作的目标是定义关键遗传 导致某些个体而非其他个体发生 ALI 的细胞危险因素。我们的假设是 促炎性中性粒细胞表型与肺功能增加有关 炎症、发生急性肺损伤的可能性更大以及更糟糕的结果 急性肺损伤。我们还假设这种促炎性中性粒细胞表型是 其特点是促炎细胞因子的产生增加， p38 和 PI3K/Akt 激酶、NF-kB 激活增加以及对糖皮质激素的抵抗。这 该计划中的四个项目和三个核心将探索假设。这 每个项目的第一个具体目标是定义人类的高和低炎症表型 中性粒细胞，如 a) PI3-K、Akt 和 NF-kB 激活（项目一）所定义； b) 激活 p38（项目二）； c) 促炎细胞因子的表达（项目三）； d) 对类固醇诱导的细胞死亡的抵抗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 风险或患有 ALI 的患者肺损伤的严重程度。每个项目的第三个具体目标是确定 a) PI3-K、Akt 和 NF-kB 激活的机制（项目一）； b) p38 激活（项目二）； c) 促炎细胞因子的产生（项目三）； d) 糖皮质激素抵抗（项目四）导致促炎性中性粒细胞表型。该 PPG 应用中提出的综合方法不仅可以深入了解引发 ALI 并导致 ALI 严重程度的细胞途径，而且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。

项目成果

Extremes of Interferon-Stimulated Gene Expression Associate with Worse Outcomes in the Acute Respiratory Distress Syndrome.

干扰素刺激的基因表达的极端与急性呼吸遇险综合征的结局较差。

• DOI: 10.1371/journal.pone.0162490
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Nick JA;Caceres SM;Kret JE;Poch KR;Strand M;Faino AV;Nichols DP;Saavedra MT;Taylor-Cousar JL;Geraci MW;Burnham EL;Fessler MB;Suratt BT;Abraham E;Moss M;Malcolm KC
• 通讯作者: Malcolm KC