The contribution of heat shock/stress pathways to acute lung injury

热休克/应激途径对急性肺损伤的影响

• 批准号: 7780051
• 负责人: JEFFREY D HASDAY
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7780051
• 关键词: A549; ATF2 gene; Acute Lung Injury; Address; Adenocarcinoma Cell; Agonist; Alveolar; Animals; Attenuated; Bacterial Pneumonia; Binding; Binding Sites; Bypass; CXC Chemokines; Cells; Chemotaxis; Complication; Computer Simulation; Consensus; Critical Illness; Cytokine Gene; Data; Diffuse; Endotoxins; Epithelial; Epithelial Cells; Epithelium; Exposure to; Face; Family; Fever; Figs - dietary; Generations; Genes; Genetic Transcription; Granulocyte-Macrophage Colony-Stimulating Factor; Heat Stress Disorders; Heat shock proteins; Heat-Shock Response; Human; Hyperoxia; IL8RB gene; Iguanas; In Vitro; Inflammation; Injury; Interleukin-8; Interleukin-8B Receptor; Interleukins; Internal Ribosome Entry Site; Interruption; Lead; Ligands; Lung; MAPK11 gene; MAPK14 gene; Modeling; Molecular; Mus; Neutrophil Infiltration; Pathway interactions; Phosphotransferases; Promoter Regions; Regulation; Repression; Research Personnel; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stimulus; Stress; System; Temperature; Testing; Tissues; Translational Repression; Translations; activating transcription factor; chemokine; granulocyte; heat-shock factor 1; in vivo; lung injury; macrophage; migration; monocyte; mouse model; neutrophil; pathogen; prevent; programs; promoter; response; transcription factor

DESCRIPTION (provided by applicant): BACKGROUND: Diffuse alveolar damage (DAD) is a common, often lethal complication in the critically ill. The mechanisms underlying DAD are incompletely understood and the strategies to prevent and treat it are suboptimal. Fever is an ancient and conserved response, which augments neutrophil recruitment and accelerates pathogen clearance, but worsens tissue injury, especially in the lung. Prolonged exposure to febrile-range hyperthermia (FRH) increases activation of several genes that promote neutrophil recruitment and activation, including the ELR+ CXC chemokines, interleukin (IL)-8, and granulocyte-macrophage colony stimulating factor (GM-CSF) as well as increasing responsiveness to a preformed IL-8 gradient in vivo. Exposure to FRH activates the heat shock (HS) response in vivo and the p38 and ERK stress kinase pathways in vitro leading to activation of the transcription factors heat shock factor-1 (HSF1), ATF2, and Elk- 1. Most of the genes for the cytokines involved in neutrophil recruitment, including the family of ELR+ CXC chemokines and their common receptor, CXCR2, and GM-CSF have binding sites for these transcription factors within their promoters. Whereas HS increases IL-8 generation when accompanied by another proinflammatory stimulus, it is not sufficient to activate IL-8 expression. HYPOTHESIS: We propose that FRH increases neutrophil delivery by increasing expression of ELR+ CXC chemokines and GM-CSF, and enhancing neutrophil CXCR2 expression and chemotaxis potential through the actions of HSF1, p38->ATF2, and ERK->Elk-1. SPECIFIC AIMS: Aim #1 will delineate the role of HSF1 and ERK in augmenting IL-8 transcription in HS-exposed cells. Aim #2 will determine how IL-8 translation bypasses the robust translational repression exerted by HS. Aim #3 will extend the IL-8 analysis to evaluate the contributions of HSF1, p38, and ERK in regulating CXC chemokines and GM-CSF in vitro and in the mouse intratracheal LPS challenge model of diffuse bacterial pneumonia and analyze how FRH increases neutrophil responsiveness to FRH. RELEVANCE: Antipyresis is difficult to achieve in the critically ill and exertional/environmental hyperthermia is often unavoidable. Ablating fever may eliminate its beneficial as well as its harmful effects. We expect that a better understanding of its molecular mechanisms will allow us to selectively block the harmful effects of fever/hyperthermia.

描述（由申请人提供）： 背景：弥漫性肺泡损伤 (DAD) 是危重患者常见的、通常致命的并发症。 DAD 的机制尚不完全清楚，预防和治疗的策略也不理想。发烧是一种古老而保守的反应，它会增加中性粒细胞的募集并加速病原体的清除，但会加剧组织损伤，尤其是肺部组织损伤。长时间暴露于发热范围的高温 (FRH) 会增加多个促进中性粒细胞募集和激活的基因的激活，包括 ELR+ CXC 趋化因子、白细胞介素 (IL)-8 和粒细胞巨噬细胞集落刺激因子 (GM-CSF) 以及增加体内对预先形成的 IL-8 梯度的反应性。暴露于 FRH 会激活体内的热休克 (HS) 反应，并在体外激活 p38 和 ERK 应激激酶途径，从而导致转录因子热休克因子-1 (HSF1)、ATF2 和 Elk-1 的激活。大多数基因参与中性粒细胞募集的细胞因子，包括 ELR+ CXC 趋化因子家族及其共同受体 CXCR2 和 GM-CSF 在其启动子内具有这些转录因子的结合位点。尽管 HS 在伴随另一种促炎刺激物时会增加 IL-8 的生成，但不足以激活 IL-8 的表达。假设：我们认为 FRH 通过增加 ELR+ CXC 趋化因子和 GM-CSF 的表达来增加中性粒细胞的输送，并通过 HSF1、p38->ATF2 和 ERK->Elk-1 的作用增强中性粒细胞 CXCR2 表达和趋化潜力。具体目标：目标 #1 将描述 HSF1 和 ERK 在增强 HS 暴露细胞中 IL-8 转录方面的作用。目标 #2 将确定 IL-8 翻译如何绕过 HS 施加的强大翻译抑制。目标 #3 将扩展 IL-8 分析，以评估 HSF1、p38 和 ERK 在体外和弥漫性细菌性肺炎的小鼠气管内 LPS 激发模型中调节 CXC 趋化因子和 GM-CSF 的贡献，并分析 FRH 如何增加中性粒细胞反应性到FRH。相关性：危重病人很难实现退烧，劳力/环境高热通常是不可避免的。退热可以消除其有益和有害的影响。我们期望更好地了解其分子机制将使我们能够选择性地阻止发烧/体温过高的有害影响。