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: 3081223
• 负责人: RALPH M SCHAPIRA
• 金额: $ 4.35万
• 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/3081223
• 关键词: alveolar macrophages; asbestos; catalase; diagnostic respiratory lavage; electron microscopy; free radical oxygen; glucose oxidase; histopathology; hydroxyl radical; lung injury; 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、肺损伤和肺纤维化的特征 尘肺被认为是由肺泡巨噬细胞介导的。 长期以来，石棉一直被认为是导致肺纤维化的原因，而 吸入性石棉纤维致肺损害的研究 RAT已经被很好地描述了。肺泡巨噬细胞可以分泌 细胞因子，如具有促分裂作用的血小板衍生生长因子(PDGF) 对间充质细胞的趋化作用，如成纤维细胞和 诱导胶原蛋白的合成。我们假设肺巨噬细胞暴露于 吸入粉尘会分泌生长因子，如PDGF，这些生长因子可以调节 肺纤维化的发展。这项拨款提案旨在建立 影响暴露大鼠肺巨噬细胞分泌PDGF的因素 体外粉尘，如基质成分(胶原蛋白、层粘连蛋白、 纤维连接蛋白)、颗粒的浓度和物理化学性质， 培养中的暴露时间，或活性氧中间体。反应性 体外氧中间体将由黄嘌呤-黄嘌呤产生 氧化酶和葡萄糖-葡萄糖氧化酶系统，并被选择性地阻断 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，巨噬细胞将被 暴露在经过铁络合剂处理的石棉中，可以防止 石棉介导的OH产生(芬顿反应)以确定是否 ···产生调节巨噬细胞分泌PDGF。老鼠会被暴露在 吸入石棉和石棉替代品以及分离和分离的巨噬细胞 培养以测定PDGF的分泌。肺损伤将用光来评估 和电子显微镜。大鼠将暴露在包有铁的石棉中 与未涂覆的纤维相比，螯合剂和PDGF的分泌。系统性 石棉暴露前用铁络合剂、过氧化氢酶、 超氧化物歧化酶和秋水仙碱将被用来确定 这些药物干预通过以下方式改善肺损伤或PDGF分泌 巨噬细胞与未经这些干预措施处理的暴露大鼠进行比较。