The spectrum of pathogenic processes that leads to pulmonary fibrosis represents a number of parallel, redundant pathways. A therapeutic intervention that targets a single step common to multiple pathways would be a welcome addition to the currently dismal state of treatment options for fibrotic lung diseases. During many inflammatory lung diseases, fibrin accumulates within the alveolar compartment, due in part to impairment of the normally fibrinolytic activity of the alveolar space. The persistence of fibrin has pathologic importance because it can serve as a scaffold on which fibroblasts invade to form collagenous scars. Using transgenic mice, we have recently found that the amount of fibrosis induced by intratracheal bleomycin is strongly influenced by the activity of the fibrinolytic system. Transgenic mice with suppressed fibrinolytic activity from over-expression of a murine plasminogen activator inhibitor-1 (PAI-1) transgene develop increased fibrosis, while mice with inactivated PAI-1 genes are relatively protected. These results, combined with the observations of others, have encouraged us to explore the strategy of increasing plasminogen activation in the alveolar space as a means to limit fibrosis during pulmonary inflammation. Although a number of approaches could be employed, we have elected to use gene transfer technology as the means to augment fibrolysis. Our experience with this modality leads us to conclude that pulmonary directed gene transfer using recombinant adenovirus-based vectors can supply the means to test our Hypothesis: Enhancement of fibrinolytic activity within the alveolar space using gene transfer technology will reduce the pulmonary fibrosis that accompanies inflammatory lung injury. We propose three Specific Aims: 1) Transfer genes for urokinase-type plasminogen activator (uPA) and PAI- 1-resistant uPA to human and murine cells in vitro and determine the effects on cell-mediated plasminogen activation and fibrin matrix degradation. 2) Transfer genes for uPA and PAI-1-resistant uPA to the lungs of mice and determine the effects on plasminogen activator activity and fibrin degradation within the alveolar space. 3) Transfer genes for uPA and PAI-1-resistant uPA to the lungs of mice and determine the effects on pulmonary fibrosis induced by inflammation. In addition to evaluating a novel therapeutic strategy for fibrotic lung diseases, our studies will provide valuable information on the relationship between fibrinolysis and fibrogenesis, and on in vivo gene transfer to the distal airspaces. A further benefit will be the provision of gene transfer technology to other Projects of this SCOR (see Project 5).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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University of Michigan Ann Arbor
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