EICOSANOIDS AND LUNG FUNCTION

类花生酸和肺功能

• 批准号: 6289940
• 负责人: Darryl C Zeldin
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289940
• 关键词: clinical research; fibroblasts; gene induction /repression; growth factor receptors; human subject; interleukin 1; lung disorder; platelet derived growth factor; prostaglandin E; protein isoforms; protein structure function; tissue /cell culture

We are investigating the role of eicosanoids in regulating platelet- derived growth factor (PDGF) receptor activity and proliferation in lung fibroblasts. Early passage human lung fibroblasts constitutively express PDGF-R and -R , and proliferate in response to PDGF ligands. Physiologic concentrations of PGE2 attenuate binding of PDGF to its receptors and decrease PDGF-stimulated 3H-thymidine. These findings are particularly important given the known effects of PGE2 on mesenchymal cell proliferation and in light of recent findings that fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize PGE2. Current efforts are focused on delineating the complex signaling mechanisms whereby PGE2 modulates PDGF receptor activity in human lung fibroblasts. In related studies, we are investigating the role of prostaglandin H synthases (PGHS) in allergen-induced pulmonary inflammation and airway hyperresponsiveness using PGHS-1 (-/-) and PGHS-2 (-/-) mice. Bronchoalveolar lavage fluid (BAL) PGE2 is significantly lower in nonimmunized PGHS-1 (-/-) mice compared to wild type or PGHS-2 (-/-) mice, but there are no significant differences in basal lung function or histopathology. Following allergen challenge, lung inflammatory indices (BALF cells, proteins, IgE and lung histopathology) are significantly greater in PGHS-1 (-/-) compared with PGHS-2 (-/-) mice, and both are far greater than in wild type mice. Both allergic PGHS-1 (-/-) and PGHS-2 (-/-) mice exhibit decreased baseline lung compliance compared with allergic wild type mice, while only allergic PGHS-1 deficient mice show increased baseline lung resistance and responsiveness to methacholine. Allergen exposure causes a modest increase in lung PGHS-2 protein and a corresponding increase in BAL fluid PGE2 in wild type mice. Thus, PGHS- 1 is the predominant enzyme that biosynthesizes PGE2 in normal mouse lung, both PGHS-1 and PGHS-2 products limit allergic lung inflammation and promote lung function, and there is a dissociation between the presence of airway inflammation and the development of airway hyperresponsiveness in PGHS-2 deficient mice. Current studies will: (a) elucidate the mechanisms whereby PGHS-derived eicosanoids modulate the lung immune response to inhaled allergens; (b) investigate the PGHS- dependent mechanisms involved in the inflammatory response to endotoxin inhalation; and (c) utilize well characterized pulmonary infectivity models to evaluate host resistance to intracellular and extracellular pathogens and to determine if there is an innate defect in T cell function in the PGHS deficient mice. - platelet derived growth factor fibroproliferative lung disease eicosanoids prostaglandins fibroblasts cyclooxygenases - Human Subjects

我们正在研究类花生酸在调节血小板衍生生长因子（PDGF）受体活性和肺成纤维细胞增殖中的作用。早期传代人肺成纤维细胞组成型表达PDGF-R和-R，并响应于PDGF配体增殖。生理浓度的PGE 2减弱PDGF与其受体的结合，并减少PDGF刺激的3 H-胸苷。鉴于已知PGE 2对间充质细胞增殖的作用，以及鉴于最近发现从特发性肺纤维化患者中分离的成纤维细胞合成PGE 2的能力降低，这些发现特别重要。目前的努力集中在描绘复杂的信号转导机制，从而PGE 2调节PDGF受体在人肺成纤维细胞的活性。在相关研究中，我们正在使用PGHS-1（-/-）和PGHS-2（-/-）小鼠研究前列腺素H结合酶（PGHS）在变应原诱导的肺部炎症和气道高反应性中的作用。与野生型或PGHS-2（-/-）小鼠相比，未免疫的PGHS-1（-/-）小鼠的支气管肺泡灌洗液（BAL）PGE 2显著较低，但在基础肺功能或组织病理学方面没有显著差异。过敏原激发后，PGHS-1（-/-）小鼠的肺部炎症指数（BALF细胞、蛋白质、IgE和肺组织病理学）显著高于PGHS-2（-/-）小鼠，且均远高于野生型小鼠。与过敏性野生型小鼠相比，过敏性PGHS-1（-/-）和PGHS-2（-/-）小鼠均表现出基线肺顺应性降低，而仅过敏性PGHS-1缺陷小鼠表现出基线肺阻力和对乙酰甲胆碱的反应性增加。变应原暴露导致野生型小鼠肺PGHS-2蛋白适度增加，BAL液PGE 2相应增加。因此，PGHS- 1是在正常小鼠肺中生物合成PGE 2的主要酶，PGHS-1和PGHS-2产物都限制过敏性肺部炎症并促进肺功能，并且在PGHS-2缺陷小鼠中气道炎症的存在与气道高反应性的发展之间存在分离。目前的研究将：（a）阐明PGHS衍生的类二十烷酸调节肺对吸入变应原的免疫应答的机制;（B）研究参与对内毒素吸入的炎症应答的PGHS依赖性机制;和（c）利用充分表征的肺感染性模型来评价宿主对细胞内和细胞外病原体的抗性，并确定PGHS缺陷小鼠中T细胞功能是否存在先天缺陷。- 血小板衍生生长因子纤维增生性肺病类花生酸类胡萝卜素成纤维细胞环加氧酶-人类