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: 7586229
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586229
• 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）是危重病患者常见的、往往致命的并发症。DAD的机制尚未完全了解，预防和治疗的策略也不理想。发热是一种古老而保守的反应，它增加了中性粒细胞的募集并加速了病原体的清除，但减少了组织损伤，特别是在肺中。长时间暴露于发热范围高热（FRH）会增加几种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），并增加对体内预先形成的IL-8梯度的反应性。暴露于FRH激活体内热休克（HS）反应和体外p38和ERK应激激酶途径，导致转录因子热休克因子-1（HSF 1）、ATF 2和Elk- 1的激活。大多数参与嗜中性粒细胞募集的细胞因子的基因，包括ELR+ CXC趋化因子家族及其共同受体CXCR 2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时增加IL-8产生，但它不足以激活IL-8表达。假设：我们认为FRH通过增加ELR+ CXC趋化因子和GM-CSF的表达增加中性粒细胞递送，并通过HSF 1、p38-> ATF 2和ERK->Elk-1的作用增强中性粒细胞CXCR 2的表达和趋化潜力。具体目的：目的#1将描述HSF 1和ERK在HS暴露细胞中增强IL-8转录的作用。目的#2将确定IL-8翻译如何绕过HS施加的强翻译抑制。目的#3将扩展IL-8分析，以评估HSF 1、p38和ERK在体外和弥漫性细菌性肺炎的小鼠气管内LPS攻击模型中调节CXC趋化因子和GM-CSF的贡献，并分析FRH如何增加中性粒细胞对FRH的反应性。相关性：在重症患者中很难实现退热，而且劳力性/环境性高热通常不可避免。发烧可以消除它的有益影响以及有害影响。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断发热/高热的有害影响。