CONTROL OF FIBRINOLYTIC PATHWAYS IN LUNG DISEASE

尿激酶(uPA)-尿激酶受体（uPAR）系统与肺部炎症和肿瘤的发病机制有关。肺上皮细胞和成纤维细胞表达uPA和uPAR，影响急性肺损伤、肺泡重塑和肺癌的进程。uPA和UPAR都参与细胞表面蛋白水解活性的定位、细胞迁移的调节和细胞增殖的控制。uPA和uPAR的表达增加与肺癌的侵袭性有关。急性呼吸窘迫综合征（ARDS）或肺间质性疾病患者肺中uPA的表达降低会加剧纤维化肺泡炎，uPA对肺成纤维细胞有丝分裂作用。目前，控制肺中uPA和uPAR表达的转录后机制尚不清楚。我们最近发现，uPA和uPAR的表达主要受细胞因子介导的uPA和uPAR mRNA稳定的转录后机制调节。uPA的转录后调控涉及uPA mRNA结合蛋白（uPA mRNABp）与uPA mRNA的66nt . 3‘非翻译区（3 ’UTR）之间的相互作用。uPAR的转录后调控涉及51 nt编码序列决定因子与uPAR mRNA结合蛋白（uPAR mRNABp）之间的相互作用。uPAR mRNABp还结合了uPAR mRNA的46 nt. 3' UTR区域，但这种相互作用在uPAR和mRNA的调控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的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瘤变和瘤变中表达。这些研究将提供关于uPA和uPAR表达在肺转录后水平调控的机制以及这些机制如何在疾病中起作用的新信息。这项工作可能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能令人满意。

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.