GROWTH FACTOR SECRETION IN DUST-INDUCED LUNG DISEASE

粉尘引起的肺病中的生长因子分泌

• 批准号: 3081220
• 负责人: RALPH M SCHAPIRA
• 金额: $ 6.34万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3081220
• 关键词: alveolar macrophages; asbestos; catalase; diagnostic respiratory lavage; electron microscopy; free radical oxygen; glucose oxidase; histopathology; hydroxyl group; platelet derived growth factor; pneumoconiosis; pollution related respiratory disorder; pulmonary fibrosis /granuloma; superoxide dismutase; xanthine oxidase

The alveolar inflammation, injury and fibrosis characteristic of the pneumoconioses are thought to be mediated by the alveolar macrophage. Asbestos has long been known to be a cause of pulmonary fibrosis and the development of lung lesions following inhalation of asbestos fibers in the rat has been well characterized. The alveolar macrophage can secrete cytokines such as platelet-derived growth factor (PDGF) which has mitogenic and chemotactic effects on mesenchymal cells such as fibroblasts and induces collagen synthesis. We hypothesize that lung macrophages exposed to inhaled dusts secrete growth factors such as PDGF which mediate the development of pulmonary fibrosis. The grant proposal seeks to establish factors that modify the secretion of PDGF by rat lung macrophages exposed to dusts in vitro such as matrix components (collagen, laminin, fibronectin), concentration and physicochemical nature of particles, exposure times in culture, or reactive oxygen intermediates. Reactive oxygen intermediates in vitro will be generated by the xanthine-xanthine oxidase and glucose-glucose oxidase systems and selectively blocked by various scavengers such as catalase, superoxide dismutase or the hydroxyl radical (OH) scavenger dimethylthiourea. In addition, macrophages will be exposed to asbestos treated with iron chelators which prevent asbestos-mediated OH production (the Fenton reaction) to determine whether OH generation modulates PDGF secretion by macrophages. Rats will be exposed to inhaled asbestos and "asbestos substitutes" and macrophages isolated and cultured to measure PDGF secretion. Lung injury will be assessed by light and electron microscopy. Rats will be exposed to asbestos coated with iron chelators and PDGF secretion compared to uncoated fibers. Systemic treatment of rats prior to asbestos exposure with iron chelators, catalase, superoxide dismutase, and colchicine will be performed to determine whether these pharmacological interventions modify lung injury or PDGF secretion by macrophages compared to exposed rats not treated with these interventions.

肺泡炎、损伤和纤维化的特点， 尘肺病被认为是由肺泡巨噬细胞介导的。 长期以来，人们都知道哮喘是肺纤维化的一个原因， 吸入石棉纤维后肺部病变的发展 大鼠已被充分表征。肺泡巨噬细胞能分泌 细胞因子如血小板衍生生长因子（PDGF），其具有促有丝分裂作用， 和对间充质细胞如成纤维细胞的趋化作用， 诱导胶原蛋白合成。我们假设肺巨噬细胞暴露于 吸入的粉尘分泌生长因子如PDGF，其介导 肺纤维化的发展。该补助金提案旨在建立 大鼠肺巨噬细胞PDGF分泌的调节因子 在体外接触粉尘如基质成分（胶原，层粘连蛋白， 纤连蛋白），颗粒的浓度和物理化学性质， 培养物中的暴露时间或活性氧中间体。反应性 氧中间体在体外会产生黄嘌呤-黄嘌呤 氧化酶和葡萄糖-葡萄糖氧化酶系统，并被 各种清除剂如过氧化氢酶、超氧化物歧化酶或羟基 自由基（OH）清除剂二甲基硫脲。此外，巨噬细胞将 接触用铁螯合剂处理的石棉， 石棉介导的OH产生（芬顿反应），以确定是否 OH产生调节巨噬细胞的PDGF分泌。老鼠会暴露在 吸入石棉和“石棉替代品”和巨噬细胞分离， 培养以测量PDGF分泌。肺损伤将通过光 和电子显微镜。老鼠会接触到涂有铁的石棉 螯合剂和PDGF分泌相比，未涂覆的纤维。系统性 用铁螯合剂，过氧化氢酶， 超氧化物歧化酶和秋水仙碱将进行，以确定是否 这些药物干预通过以下方式改变肺损伤或PDGF分泌： 与未用这些干预措施处理的暴露大鼠相比，