Pleural injury often resolves with remodeling of the pleural surfaces, which in severe cases leads to pleural fibrosis (PF) and fibrothorax. These sequellae are associated with respiratory impairment, reduced quality of life and increased mortality. PF with lung restriction is often seen in medical practice but current treatment is unsatisfactory and effective pharmacotherapy is not available. PF is characterized by aberrant local fibrin deposition and proliferation of alpha-smooth muscle actin (?-SMA) expressing myofibroblasts. The expansion of myofibroblasts is largely due to mesenchymal transition (MT) of resident pleural mesothelial cells (PMC), termed MesoMT. These motile, matrix-producing cells are largely responsible for thickening of the pleura; pleural rind formation. MesoMT and PF are linked to fibrinolytic pathways, as proteases involved in fibrin degradation induce MesoMT. We recently reported that deficiency of plasminogen activator inhibitor (PAI)-1, the principal inhibitor of urokinase plasminogen activator (uPA) and tissue PA (tPA), increases plasmin activity and significantly worsens pleural injury. We also found that uPA and plasmin potently induce MesoMT. uPA- and plasmin-mediated MesoMT involves activation of glycogen synthase kinase (GSK)-3?, a new and promising target for the treatment of PF. Further, our preliminary studies show that GSK-3? inhibition with a novel inhibitor, 9ING41, significantly attenuates the progression of pleural injury and remodeling. Based on these observations and strong preliminary data, we strongly infer that uPA and plasmin and their activation of GSK-3?, substantively contribute to the progression of PF. In this project, we will test the central hypothesis that fibrinolysin-mediated changes and activation of GSK-3? are important steps that regulate PMC phenotype and pleural injury outcomes including PF. Our objective is to determine the mechanism by which fibrinolytic proteases, including uPA and plasmin, induce MesoMT and define their contribution to fibrosing pleural injury. We will also define the contribution of increased GSK-3? signaling to the progression of PF.
Our specific aims are: 1) to define protease-receptor interactions by which the fibrinolytic system regulates MesoMT and pleural remodeling, 2) to determine the mechanism by which GSK-3? signaling is regulated in uPA and plasmin- induced MesoMT and 3) to determine the contribution of GSK-3? to the progression of pleural injury. We will use new models of fibrosing pleural injury and empyema, mice with mesothelial labelling for fate-mapping analyses, molecular, biochemical, histology and immunohistochemical techniques with which we have expertise, state of the art CT imaging and pulmonary function analyses to accomplish these aims. We will test whether new therapeutic agents including inhibitors of GSK-3? signaling effectively block the development of PF. These studies will address gaps in our understanding of the pathogenesis of PF and thereby advance the field. The proposal may also identify promising novel interventions that, if successful, could be further developed to ultimately improve outcomes of patients with fibrosing pleural injury.
Scarring at the lung surface; pleural fibrosis, can cause severe respiratory impairment for which current treatment is unsatisfactory. Fibrinolytic proteases; urokinase and plasmin, induce mesothelial cell plasticity which promotes pleural fibrosis. We will determine mechanisms through which these proteins promote pleural fibrosis and test new interventions to prevent its development after pleural injury.
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