Anti-Inflammatory PAF Acetylhydrolase in Lung Injury

肺损伤中的抗炎 PAF 乙酰水解酶

• 批准号: 6537918
• 负责人: KATHERINE M HOWARD
• 金额: $ 18.06万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537918
• 关键词: alveolar macrophages; carboxylic ester hydrolases; cell type; eicosanoids; enzyme mechanism; hyperoxia; inflammation; laboratory mouse; laboratory rat; lipopolysaccharides; lung injury; neutrophil; phospholipase A2; platelet activating factor; posttranslational modifications; protein localization; receptor; transcription factor

Plasma-type platelet-activating factor acetylhydrolase is a distinct Ca+2- independent phospholipase A2 enzyme specific for the inactivation of platelet-activating factor (PAF) and PAF- like phospholipids. Thus, PAF acetylhydrolase plays a crucial role in inactivating a potent inflammatory mediator implicated in the initiation and propagation of acute lung injury. This anti- inflammatory property of PAF acetylhydrolase has lead to the therapeutic investigation of PAF acetylhydrolase in a wide range of inflammatory diseases including asthma, Adult Respiratory Distress Syndrome, diabetes, pancreatitis, and vascular and heart disease. The objective of the proposed research is to investigate the cellular and molecular mechanisms involved in the expression and regulation of PAF acetylhydrolase in rat models of acute lung injury. Lung tissue PAF acetylhydrolase expression is dramatically increased in response to in vivo inflammatory challenge. Three closely related Specific Aims will lead to the localization and characterization of PAF acetylhydrolase- expressing cells; the elucidation of the mechanisms involved in PAF acetylhydrolase up-regulation; and the determination of the physiological consequences of increased PAF acetylhydrolase in resolving and limiting lung injury. First, a detailed localization and characterization of PAF acetylhydrolase in normal lung and in response to lung injury will be performed. These experiments in whole animals will explore the differential expression of PAF acetylhydrolase in resident lung macrophages and granulocytes. Granulocytes, predominately comprised of neutrophils, appear to have the capacity to deliver this potent anti-inflammatory agent to sites of inflammation. Second, the involvement of PAF, the PAF receptor, and STAT transcription factors in PAF acetylhydrolase up-regulation will be examined. These experiments will determine the effects on PAF acetylhydrolase expression resulting from the administration of PAF and PAF receptor antagonists and in mice genetically lacking the PAF receptor. Third, the physiological consequences of up- regulated PAF acetylhydrolase expression in lung injury will be investigated by assessing the in vivo PAF-degrading capacity of the compromised lung and determining the effects on the lung inflammatory sequelae in response to exogenous PAF acetylhydrolase administration. Through the logical design of the proposed studies, novel and important information will be gained that will significantly advance our understanding of the cell biology of this important anti-inflammatory enzyme.

血浆型血小板活化因子乙酰水解酶是一种独特的Ca+2非依赖性磷脂酶A2，对血小板活化因子（PAF）和PAF样磷脂的失活具有特异性。 因此，PAF乙酰水解酶在灭活与急性肺损伤的起始和传播有关的强效炎症介质中起着至关重要的作用。 PAF乙酰水解酶的这种抗炎性质已经导致PAF乙酰水解酶在广泛的炎性疾病中的治疗研究，所述炎性疾病包括哮喘、成人呼吸窘迫综合征、糖尿病、胰腺炎以及血管和心脏疾病。 本研究的目的是探讨PAF乙酰水解酶在大鼠急性肺损伤模型中表达和调控的细胞和分子机制。 肺组织PAF乙酰水解酶表达在体内炎症反应中显著增加。 三个密切相关的特定目的将导致PAF乙酰水解酶表达细胞的定位和表征;阐明PAF乙酰水解酶上调所涉及的机制;以及确定PAF乙酰水解酶增加在解决和限制肺损伤中的生理后果。 首先，将进行PAF乙酰水解酶在正常肺和肺损伤中的详细定位和表征。这些在整个动物中的实验将探索PAF乙酰水解酶在驻留肺巨噬细胞和粒细胞中的差异表达。 粒细胞主要由中性粒细胞组成，似乎具有将这种强效抗炎剂递送至炎症部位的能力。 其次，PAF，PAF受体，和STAT转录因子在PAF乙酰水解酶上调的参与将被检查。这些实验将确定PAF和PAF受体拮抗剂给药对PAF乙酰水解酶表达的影响，以及遗传缺乏PAF受体的小鼠。 第三，将通过评估受损肺的体内PAF降解能力并确定响应于外源性PAF乙酰水解酶施用对肺部炎症后遗症的影响来研究肺损伤中上调的PAF乙酰水解酶表达的生理后果。 通过拟议研究的逻辑设计，将获得新的和重要的信息，这将大大促进我们对这种重要抗炎酶的细胞生物学的理解。