EICOSANOIDS AND LUNG FUNCTION

我们正在研究类二十烷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性地表达PDGF-R和-R，并在PDGF配体的作用下增殖。PGE2的生理浓度减弱PDGF与其受体的结合，减少PDGF刺激的3h -胸腺嘧啶。考虑到PGE2对间充质细胞增殖的已知作用，以及最近从特发性肺纤维化患者分离的成纤维细胞合成PGE2的能力降低，这些发现尤为重要。目前的工作重点是描述PGE2调节人肺成纤维细胞PDGF受体活性的复杂信号机制。在相关研究中，我们正在利用PGHS-1（-/-）和PGHS-2（-/-）小鼠研究前列腺素H合成酶（PGHS）在过敏原诱导的肺部炎症和气道高反应性中的作用。未免疫PGHS-1（-/-）小鼠的支气管肺泡灌洗液（BAL） PGE2明显低于野生型或PGHS-2（-/-）小鼠，但在肺基础功能和组织病理学上无显著差异。致敏原激发后，PGHS-1（-/-）小鼠的肺部炎症指数（BALF细胞、蛋白、IgE和肺组织病理学）明显高于PGHS-2（-/-）小鼠，且两者均远高于野生型小鼠。与过敏野生型小鼠相比，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缺陷小鼠表现出基线肺抵抗和对甲胆碱的反应性增加。在野生型小鼠中，过敏原暴露导致肺PGHS-2蛋白适度增加，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炎症并促进肺功能，PGHS-2缺陷小鼠气道炎症的存在与气道高反应性的发展之间存在解离。目前的研究将：(a)阐明pghs衍生的二十烷酸调节肺部对吸入过敏原的免疫反应的机制；(b)研究内毒素吸入引起炎症反应的PGHS依赖性机制；(c)利用特征良好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生性肺病类二十烷类前列腺素成纤维细胞环加氧酶

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