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

我们正在研究类二十烷酸在调节肺成纤维细胞血小板衍生生长因子（PDGF）受体活性和增殖中的作用。早期传代的人肺成纤维细胞组成型表达PDGF-R和-R，并响应PDGF配体而增殖。 PGE2 的生理浓度会减弱 PDGF 与其受体的结合并减少 PDGF 刺激的 3H-胸苷。鉴于 PGE2 对间充质细胞增殖的已知影响，以及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 PGE2 的能力下降，这些发现尤其重要。目前的工作重点是描绘 PGE2 调节人肺成纤维细胞中 PDGF 受体活性的复杂信号传导机制。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 合酶 (PGHS) 在过敏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 PGHS-1 (-/-) 小鼠的支气管肺泡灌洗液 (BAL) PGE2 显着降低，但基础肺功能或组织病理学没有显着差异。过敏原攻击后，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）显着高于 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，而只有过敏性 PGHS-1 缺陷型小鼠表现出基线肺阻力和对乙酰甲胆碱的反应性增加。暴露于过敏原会导致野生型小鼠肺 PGHS-2 蛋白适度增加，并且 BAL 液 PGE2 相应增加。因此，PGHS-1是正常小鼠肺中生物合成PGE2的主要酶，PGHS-1和PGHS-2产物均能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关联。目前的研究将： (a) 阐明 PGHS 衍生的类二十烷酸调节肺部对吸入过敏原的免疫反应的机制； (b) 研究内毒素吸入炎症反应中涉及的 PGHS 依赖性机制； (c) 利用充分表征的肺部感染模型来评估宿主对细胞内和细胞外病原体的抵抗力，并确定 PGHS 缺陷小鼠的 T 细胞功能是否存在先天缺陷。 - 血小板衍生生长因子、纤维增殖性肺病、类二十烷酸、前列腺素、成纤维细胞、环氧合酶 - 人类受试者