CONTROL OF FIBRINOLYTIC PATHWAYS IN LUNG DISEASE

点击翻译按钮获取中文摘要

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.