CONTROL OF FIBRINOLYTIC PATHWAYS IN LUNG DISEASE

尿激酶（uPA）-尿激酶受体（uPAR）系统参与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，并影响急性肺损伤、肺泡重塑和肺癌的过程。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的高表达与肺癌的侵袭性有关。在患有ARDS或间质性肺疾病的患者的肺中，uPA的表达降低会增强纤维化肺泡炎，并且uPA对肺成纤维细胞具有促有丝分裂作用。目前，对控制uPA和uPAR在肺中表达的转录后机制知之甚少。我们最近发现uPA和uPAR的表达主要受转录后机制的调节，该机制涉及细胞因子介导的uPA和uPAR mRNA的稳定。uPA的转录后调节涉及uPA mRNA结合蛋白（uPA mRNABP）与66 nt之间的相互作用。Upa mRNA的3'非翻译区（3 'UTR）。uPAR的转录后调节涉及51 nt之间的相互作用。编码序列决定簇和uPAR mRNA结合蛋白（uPAR mRNABP）。uPAR mRNABP也结合46 nt。在uPAR mRNA的3' UTR区，这种相互作用的作用，但在调节uPAR和mRNA的作用目前还不清楚。利用分子和生物化学方法，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的uPA和uPAR转录后调节中的作用。利用免疫组化分析和原位杂交分析肺组织，我们将确定这些蛋白质是如何表达在肺部炎症和肿瘤和肿瘤。这些研究将提供有关uPA和uPAR表达在肺中转录后水平调节的机制以及这些机制如何在疾病中起作用的新信息。这项工作可能会提出新的治疗方法，目前的治疗往往是不满意的各种炎症或肿瘤性肺部疾病。

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.