EICOSANOIDS AND LUNG FUNCTION
类花生酸和肺功能
基本信息
- 批准号:6289940
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Darryl C Zeldin其他文献
Darryl C Zeldin的其他文献
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{{ truncateString('Darryl C Zeldin', 18)}}的其他基金
CARDIAC CYTOCHROME P450 ARACHIDONIC ACID EPOXYGENASE PATHWAY
心脏细胞色素 P450 花生四烯酸环氧化酶途径
- 批准号:
6289939 - 财政年份:
- 资助金额:
-- - 项目类别:
Arachidonic acid metabolism by murine CYP2C isoforms
小鼠 CYP2C 亚型对花生四烯酸的代谢
- 批准号:
6413417 - 财政年份:
- 资助金额:
-- - 项目类别:
Characterization And Functional Significance Of P450 Ara
P450 Ara 的表征及功能意义
- 批准号:
7168262 - 财政年份:
- 资助金额:
-- - 项目类别:
Alterations In Pulmonary Immune Function And Host Resist
肺免疫功能和宿主抵抗力的改变
- 批准号:
7168264 - 财政年份:
- 资助金额:
-- - 项目类别:
Alterations In Pulmonary Immune Function And Host Resistance In COX Null Mice
COX 无效小鼠肺免疫功能和宿主抵抗力的变化
- 批准号:
8553686 - 财政年份:
- 资助金额:
-- - 项目类别:
Program in Clinical Research, Clinical Support Services and Clinical Training
临床研究、临床支持服务和临床培训项目
- 批准号:
7734571 - 财政年份:
- 资助金额:
-- - 项目类别:
Characterization And Functional Significance Of P450 Arachidonate Epoxygenases
P450 花生四烯酸环氧合酶的特征和功能意义
- 批准号:
10919036 - 财政年份:
- 资助金额:
-- - 项目类别:
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