Plasminogen activation system in pulmonary fibrosis

(申请人摘要)随后出现的肺纤维化的严重程度 博莱霉素对小鼠的给药可以通过操纵 纤溶酶原激活系统。促进纤溶酶形成的干预措施 减少受伤后积累的胶原蛋白的程度。这种抗肝纤维化的药 在其他器官中也看到了这种效果，表明 对纤溶酶原激活系统的操纵可以提供一种限制 特发性肺纤维化期间发生的纤维化。长期的 我们调查的目标是：a)了解 纤溶酶原激活系统及其导致肺损伤的过程 纤维化，以及b)评估纤溶酶原激活系统在 患有特发性肺纤维化的人。这项建议的具体施舍 是为了1)确定增加纤溶酶原的有益影响 激活剂活性从博莱霉素模型扩展到其他类型的 纤维肺损伤；2)测定血浆纤溶酶原的空间分布 肺损伤和肺损伤过程中肺组织中激活物活性的变化 3)筛选和评估肝纤维化的可能机制。 纤溶酶原激活系统影响肺纤维化的发展； 4)确定人类特发性肺纤维化是否受 在人PAM基因启动子区域发现特定的多态；以及 5)确定从特发性肺组织分离的成纤维细胞 肺纤维化与纤溶酶原有关的表型改变 激活系统。这些研究将使用多方面的方法，采用 肺纤维化的免疫模型及患者肺组织和细胞 患有特发性肺纤维化。这些研究将使用分子 生物学和分子遗传学技术，新的组织学方法 蛋白水解酶活性定位和基因芯片芯片技术。完成 这些研究应该提供科学基础，以此为基础 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.