Plasminogen activation system in pulmonary fibrosis

（申请人的摘要）以下肺纤维化的严重性 博来霉素对小鼠的给药可受操作的影响， 纤溶酶原激活系统。增强纤溶酶形成的干预措施 减少损伤后胶原蛋白的积累。这种抗纤维化 在其他器官中也观察到的效应表明， 操纵纤溶酶原激活系统可以提供一种手段 在特发性肺纤维化期间发生的纤维化。长期 我们调查的目的是：a）了解 纤溶酶原激活系统和导致肺纤维化的过程 B）评估纤溶酶原激活系统在纤维化中的作用， 患有特发性肺纤维化的人。本提案的具体内容 是1）确定增加纤溶酶原的有益作用是否 激活剂活性超出博来霉素模型扩展到其他类型的 纤维化肺损伤; 2）确定血浆蛋白的空间分布？伊利诺根 肺损伤过程中肺组织中的激活剂活性， 纤维化; 3）筛选和评估可能的机制， 纤溶酶原激活系统影响肺纤维化的发生发展; 4)确定人类特发性肺纤维化是否受 在人PAM基因的启动子区中发现的特异性多态性;和 5)确定从特发性肺结核患者的肺中分离的成纤维细胞是否 肺纤维化具有关于纤溶酶原的改变的表型 激活系统这些研究将采用多方面的方法， 肺纤维化的小鼠模型和来自患者的肺组织和细胞 特发性肺纤维化调查将使用分子 生物学和分子遗传技术，新的组织学方法， 定位蛋白酶活性和基因芯片微阵列技术。完成 这些研究应该提供科学基础， 治疗特发性肺纤维化患者的新策略。

(Applicant's Abstract) The severity of pulmonary fibrosis that follows administration of bleomycin to mice can be influenced by manipulations of the plasminogen activation system. Interventions that enhance plasmin formation reduce the extent of collagen that accumulates after injury. This anti-fibrotic effect, which has been seen in other organs as well, suggests that manipulation of the plasminogen activation system may provide a means to limit the fibrosis that occurs during idiopathic pulmonary fibrosis. The long-term objectives of our investigations are to a) understand the relationship between the plasminogen activation system and the processes that lead to pulmonary fibrosis, and b) evaluate the role of the plasminogen activation system in humans with idiopathic pulmonary fibrosis. The Specific Alms of this proposal are to 1) determine whether the beneficial effects from increasing plasminogen activator activity extend beyond the bleomycin model to other types of fibrotic lung injury; 2) determine the spatial distribution of plasn?llinogen activator activity in lung tissue during the processes of lung injury and fibrosis; 3) screen for and evaluate possible mechanisms by which the plasminogen activation system effects the development of pulmonary fibrosis; 4) determine if idiopathic pulmonary fibrosis in humans is influenced by a specific polymorphism found in the promoter region of the human PAM gene; and 5) determine if fibroblasts isolated from lungs of patients with idiopathic pulmonary fibrosis have an altered phenotype regarding the plasminogen activation system. These studies will use a multifaceted approach that employs munine models of pulmonary fibrosis and lung tissue and cells from patients with idiopathic pulmonary fibrosis. The investigations will use molecular biology and molecular genetic techniques, novel histological methods for localizing protease activity, and gene chip microarray technology. Completion of these studies should provide the scientific foundation on which to base a new strategy to treat patients with idiopathic pulmonary fibrosis.