Anti-Inflammatory PAF Acetylhydrolase in Lung Injury

肺损伤中的抗炎 PAF 乙酰水解酶

• 批准号: 6382832
• 负责人: KATHERINE M HOWARD
• 金额: $ 16.95万
• 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/6382832
• 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不依赖于Ca+2的磷脂酶A2酶，专门用于血小板活化因子（PAF）和PAF样磷脂的失活。因此，PAF乙酰水解酶在灭活一种与急性肺损伤的发生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特性导致了PAF乙酰水解酶在广泛的炎症性疾病中的治疗研究，包括哮喘、成人呼吸窘迫综合征、糖尿病、胰腺炎、血管和心脏病。本研究旨在探讨急性肺损伤大鼠模型中PAF乙酰水解酶的表达和调控的细胞和分子机制。肺组织PAF乙酰水解酶的表达在体内炎症反应中显著增加。三个密切相关的特异性目标将导致PAF乙酰水解酶表达细胞的定位和表征；PAF乙酰水解酶上调机制的阐明；以及确定PAF乙酰水解酶增加在缓解和限制肺损伤方面的生理后果。首先，详细定位和表征PAF乙酰水解酶在正常肺和响应肺损伤将进行。这些全动物实验将探讨PAF乙酰水解酶在常驻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，似乎有能力将这种有效的抗炎剂输送到炎症部位。其次，将研究PAF、PAF受体和STAT转录因子在PAF乙酰水解酶上调中的作用。这些实验将确定PAF和PAF受体拮抗剂在遗传上缺乏PAF受体的小鼠中对PAF乙酰水解酶表达的影响。第三，通过评估受损肺的体内PAF降解能力和确定外源性PAF乙酰水解酶对肺部炎症后遗症的影响，研究PAF乙酰水解酶表达上调在肺损伤中的生理后果。通过提出的研究的逻辑设计，将获得新的和重要的信息，这将大大推进我们对这种重要的抗炎酶的细胞生物学的理解。