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

描述（由申请人提供）：背景：弥漫性肺泡损伤（DAD）是危重患者常见的致命并发症。DAD的机制尚不完全清楚，预防和治疗的策略也不够理想。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，加速了病原体的清除，但也加重了组织损伤，尤其是肺组织损伤。长期暴露于发热范围内的高温（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），以及增加体内对预先形成的IL-8梯度的反应性。暴露于FRH可激活体内热休克（HS）反应和体外p38和ERK应激激酶途径，从而激活转录因子热休克因子-1 （HSF1）、ATF2和Elk- 1。大多数参与中性粒细胞募集的细胞因子基因，包括ELR+ CXC趋化因子家族及其共同受体CXCR2和GM-CSF，在其启动子内都有这些转录因子的结合位点。虽然HS在另一种促炎刺激下会增加IL-8的产生，但不足以激活IL-8的表达。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传递，并通过HSF1、p38->ATF2和ERK->Elk-1的作用增强中性粒细胞CXCR2的表达和趋化潜能。特异性目的：目的1将描述HSF1和ERK在增加hs暴露细胞中IL-8转录中的作用。目的2将确定IL-8的翻译如何绕过HS施加的强大的翻译抑制。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弥漫性细菌性肺炎LPS刺激模型中调节CXC趋化因子和GM-CSF中的作用，并分析FRH如何增加中性粒细胞对FRH的反应性。相关性：在危重患者中很难实现退热，而体力/环境热疗通常是不可避免的。消融热既可以消除其有益的影响，也可以消除其有害的影响。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断发烧/高温的有害影响。

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.