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（爸爸）是常见的，经常发生致命的并发症。爸爸的机制尚不完全理解，预防和治疗它的策略是最佳的。发烧是一种古老而保守的反应，可增强中性粒细胞的募集并加速病原体清除，但会使组织损伤恶化，尤其是在肺中。长时间暴露于高热范围高温（FRH）增加了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，白介素（IL）-8和粒细胞 - 摩托噬细胞群刺激因子（GM-CSF）以及对预先成熟的响应能力，并在VIV上增加了IL-8-8。暴露于FRH会激活体内的热休克（HS）反应，以及p38和ERK胁迫激酶途径在体外激活转录因子热休克因子1（HSF1），ATF2和ELK-1。这些转录因子在其启动子中的结合位点。当HS伴随着另一种促炎刺激时，HS会增加IL-8的产生，而激活IL-8表达不足以激活IL-8。假设：我们提出，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递送，并通过HSF1，p38-> atf2和erk-> elk-> elk-> Elk-1的作用来增强中性粒细胞CXCR2的表达和趋化性。具体目的：AIM＃1将描述HSF1和ERK在增强HS暴露细胞中IL-8转录中的作用。 AIM＃2将决定IL-8翻译如何绕过HS施加的强大翻译抑制。 AIM＃3将扩展IL-8分析，以评估HSF1，p38和ERK在体外和小鼠气管内LPS LPS挑战模型中弥漫细菌性肺炎挑战模型的HSF1，p38和ERK的贡献，并分析FRH如何增加中性粒细胞对FRH的反应。相关性：在重症患病中很难实现抗精性，而劳累/环境高温通常是不可避免的。消融发烧可能会消除其有益及其有害影响。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止发烧/热疗的有害影响。