p38MAP kinase-dependent mechanisms of fever-enhanced acute lung injury

发热增强急性肺损伤的 p38MAP 激酶依赖性机制

• 批准号: 8911921
• 负责人: JEFFREY D HASDAY
• 金额: $ 9.96万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911921
• 关键词: Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Affinity; Agonist; Antibiotic Resistance; Body Temperature; Cell Nucleus; Cell physiology; Data; Docking; Endothelial Cells; Environmental air flow; Epithelial; Event; Exposure to; Feline Panleukopenia; Fever; Gene Deletion; Goals; HSPB1 gene; Health; Heat Stroke; Heat-Shock Proteins 70; Histones; Human; Hyperthermia; Immune; Immune response; In Vitro; Induced Hyperthermia; Indwelling Catheter; Inflammation; Inflammatory; Injury; Intensive Care Units; Intervention; Knowledge; Lead; Location; Lung; Lung Inflammation; MAP-kinase-activated protein kinase 2; MAPK11 gene; MAPK14 gene; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Conformation; Mus; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Permeability; Phase; Phosphorylation; Phosphotransferases; Play; Pneumonia; Principal Investigator; Process; Proteins; Protocols documentation; Recovery; Relative (related person); Reporting; Research; Research Proposals; Role; SB 203580; Scaffolding Protein; Signal Pathway; Signal Transduction; Stress; Structure; Testing; Tidal Volume; Tissues; Toll-like receptors; Vascular Endothelium; Work; Yoga; base; endothelial dysfunction; extracellular; human MAPK14 protein; hyperthermia treatment; improved; in vivo; inhibitor/antagonist; innate immune function; lung injury; malignant muscle neoplasm; mitogen-activated protein kinase p38; mortality; mouse model; neutrophil; novel; novel therapeutics; pathogen; therapeutic target; therapy development; upstream kinase

DESCRIPTION (provided by applicant): This is a competitive renewal application to extend ongoing research by the co-Principal Investigators that is focused on the effects of fever and fever suppression on acute lung injury (ALI). Despite the general acceptance of low tidal volume ventilation for support of patients with ALI, mortality in such patients remains ~40%. We identified fever/hyperthermia as another potentially important contributor to ARDS pathogenesis. Fever is reported to occur in about half of patients admitted to intensive care units and in up to 90% of those with ALI/ARDS. ARDS is characterized by neutrophil-rich inflammation, loss of endothelial barrier, and epithelial injury. Our previous studies show that exposure to hyperthermia in the febrile range (FRH, ~39.5oC) profoundly augments each of these pathogenic processes. The current application proposes a mechanistic study that focuses on the role of p38 mitogen-activated protein kinase (MAPK)-dependent mechanisms of FRH- augmented ALI. We have shown that exposure to FRH augments innate immune function in part by enhancing neutrophil (PMN) recruitment. This effect accelerates pathogen clearance, but also increases collateral tissue injury, especially in the lung. Based on new data, this proposal focuses on the central role of pulmonary vascular endothelium and the stress-activated MAPK, p38. Preliminary data suggests that (1) FRH directly activates p38 at least in part through autophosphorylation and (2) that FRH directly alters p38 conformation, kinase activity, cellular localization, and substrate selectivity. This proposal will test the following hypotheses: (1) FRH activates p38 through multiple pathways including through a conformational change in p38 that facilitates its autophosphorylation and by activating upstream kinases; (2) the FRH-induced conformational changes in p38 will result in distinct patterns of p38 intermolecular docking, subcellular distribution, and downstream signaling events, which will uniquely modify downstream substrate phosphorylation patterns with important consequences for lung inflammation and injury; and (3) in the patient with ALI and fever, inhibition of p38 or downstream signaling pathways will improve outcome better than suppressing fever. We will use primary cultured HMVEC- Ls and mouse models of ALI to: (1) elucidate the molecular mechanisms by which FRH activates p38, (2) analyze how FRH modifies p38 subcellular distribution and substrate phosphorylation profile, and (3) test the potential of p38 signaling pathway blockade to reduce FRH-augmented lung injury without impairing pathogen clearance. We expect that the results of these studies will clarify the mechanisms of FRH-induced p38 signaling relevant to ALI and provide essential information about disproportionate substrate phosphorylation that will identify alternative therapeutic targets to test in ALI/ARDS. We expect that these findings will have wider applications in mitigating inflammation and injury in other tissues as well.

描述（由申请人提供）：这是一种竞争性更新应用，以扩展联合主要研究人员正在进行的研究，该研究的重点是发烧和发烧抑制对急性肺损伤（ALI）的影响。尽管普遍接受低潮汐量通气以支持ALI患者，但此类患者的死亡率仍约40％。我们确定发烧/热疗是促成ARDS发病机理的另一个潜在的重要促进者。据报道，大约一半的重症监护病房的患者发生发烧，其中多达90％患有ALI/ARD的患者。 ARDS的特征是富含中性粒细胞的炎症，内皮屏障的丧失和上皮损伤。我们先前的研究表明，在高热范围内暴露于热疗（FRH，〜39.5oC）会深刻地增加了这些病原过程的每一个。当前的应用提出了一项机械研究，该研究重点介绍了p38丝裂原激活的蛋白激酶（MAPK）依赖性ALI的机制的作用。我们已经表明，通过增强中性粒细胞（PMN）募集，暴露于FRH会增加先天免疫功能。这种作用加速了病原体清除率，但也会增加附带组织损伤，尤其是在肺中。基于新数据，该提案着重于肺血管内皮和应力激活的MAPK的核心作用，P38。初步数据表明，（1）FRH至少通过自磷酸化直接激活p38，并且（2）FRH直接改变了p38构象，激酶活性，细胞定位和底物选择性。该建议将检验以下假设： （1）FRH通过多种途径激活p38，包括通过p38的构象变化来促进其自磷酸化并激活上游激酶； （2）FRH诱导的p38中的构象变化将导致p38分子间对接，细胞亚分布和下游信号事件的不同模式，这将唯一地修改下游底物磷酸化模式，具有对肺炎症和受伤的重要后果； （3）在ALI和发烧的患者中，抑制p38或下游信号通路将比抑制发烧更好地改善预后。 We will use primary cultured HMVEC- Ls and mouse models of ALI to: (1) elucidate the molecular mechanisms by which FRH activates p38, (2) analyze how FRH modifies p38 subcellular distribution and substrate phosphorylation profile, and (3) test the potential of p38 signaling pathway blockade to reduce FRH-augmented lung injury without impairing pathogen clearance.我们预计这些研究的结果将阐明与ALI相关的FRH诱导的p38信号传导的机制，并提供有关不成比例的底物磷酸化的基本信息，这些信息将确定在ALI/ARDS中测试的替代性治疗靶标。我们预计这些发现在缓解其他组织的炎症和损伤方面也将有更广泛的应用。