CONTROL OF FIBRINOLYTIC PATHWAYS IN LUNG DISEASE

尿激酶型纤溶酶原激活剂(UPA)-尿激酶型受体(UPAR)系统参与了肺部炎症和肿瘤的发病机制。肺上皮细胞和成纤维细胞表达uPA和uPAR，影响急性肺损伤、肺泡重塑和肺癌的发病过程。UPA和uPAR均参与细胞表面蛋白分解活性的定位、细胞迁移的调控和细胞增殖的调控。UPA和uPAR的高表达与肺癌的侵袭性有关。急性呼吸窘迫综合征或间质性肺疾病患者肺组织中uPA的低表达加剧了纤维化的肺泡炎，并且uPA对肺成纤维细胞是有丝分裂的。目前，控制肺中uPA和uPAR表达的转录后机制还知之甚少。我们最近发现，uPA和uPAR的表达主要受转录后机制的调控，该机制涉及细胞因子介导的uPA和uPAR基因的稳定。UPA的转录后调控涉及uPA mRNA结合蛋白(UPA MRNABp)与66个核苷酸之间的相互作用。UPAR的转录后调控涉及51个核苷酸的编码序列决定簇和一个uPAR mRNA结合蛋白(UPAR MRNABp)之间的相互作用，uPAR的mRNABp也与uPAR mRNA的46个核苷酸3‘非翻译区结合，但这种相互作用在调控uPAR和mRNA中的作用目前尚不清楚。利用分子和生化方法，我们将确定这些新的uPA和uPAR mRNA结合蛋白在人肺上皮细胞和成纤维细胞对uPA和uPAR转录后调控中的作用。利用肺组织的免疫组织化学分析和原位杂交分析，我们将确定这些蛋白如何在肺部炎症和肿瘤以及肿瘤中表达。这些研究将提供关于肺中uPA和uPAR表达在转录后水平调节的机制(S)以及这些机制在疾病中如何运作的新信息。这项工作可能会为各种炎症性或肿瘤性肺部疾病提供新的治疗方法，目前的治疗方法往往不令人满意。

The urokinase (uPA)-urokinase receptor (uPAR) system has been implicated in the pathogenesis of pulmonary inflammation and neoplasia. Lung epithelial and fibroblasts express uPA and uPAR and influence the course of acute lung injury, alveolar remodeling and lung cancer. Both uPA and UPAR are involved in localization of cell surface proteolytic activity, regulation of cell migration and control of cellular proliferation. Increased expression of uPA and uPAR are associated with invasiveness of lung cancer. Depressed expression of uPA in the lungs of patients with ARDS or interstitial lung diseases potentiates fibrosing alveolitis and uPA is mitogenic for lung fibroblasts. Post-transcriptional mechanisms that control expression of uPA and uPAR in the lungs are, at this time, poorly understood. We recently found that uPA and uPAR expression are predominantly regulated by a post- transcriptional mechanism involving cytokine mediated stabilization of uPA and uPAR mRNA. Post-transcriptional regulation of uPA involves an interaction between a uPA mRNA binding protein (uPA mRNABp) and the 66 nt. 3' untranslated region (3 'UTR) of Upa mRNA. Post-transcriptional regulation of uPAR involves an interaction between a 51 nt. Coding sequence determinant and a uPAR mRNA binding protein (uPAR mRNABp) . The uPAR mRNABp also binds a 46 nt. 3' UTR region of uPAR mRNA, but the role of this interaction in regulation of uPAR and mRNA is currently unknown. Using molecular and biochemical approaches, we will determine the role of these novel uPA and uPAR mRNA binding proteins in the post- transcriptional regulation of uPA and uPAR by human lung epithelial cells and fibroblasts. Using immunohistochemical analyses and in situ hybridization analyses of lung tissues, we will determine how these proteins are expressed in lung inflammation and neoplasia and neoplasia. These studies will provide novel information about the mechanism(s) by which uPA and uPAR expression is regulated at the post-transcriptional level in the lung and how these mechanisms operate in disease. This work may suggest new therapeutic approaches to a variety of inflammatory or neoplastic lung diseases for which current therapy is often unsatisfactory.