The outlined proposal is designed as a training program that builds on prior experiences and ultimately leads to a career of independent research. Included in this program for the applicant is the introduction of new experimental techniques, investigation of a new area of basic science, and interaction with a new mentor. The research project will investigate an important aspect of the development of pulmonary fibrosis. Pulmonary fibrosis has been shown to occur in conjunction with depressed alveolar plasminogen activator activity. This impaired activity occurs from an imbalance between urokinase-type plasminogen activator (uPA) and its major inhibitor, plasminogen activator inhibitor-1 (PAI-1). Enhancing alveolar plasminogen activator activity through various means including targeted deletion of the PAI-1 gene or adenoviral-mediated gene transfer of the uPA cDNA results in decreased collagen accumulation following a fibrogenic insult. The mechanism by which enhanced alveolar plaminogen activator activity mitigates fibrosis is unknown. Insights into this mechanism may lead to new treatments. Of several possibilities, two mechanisms are most likely. The hypothesis of this proposal is that enhanced alveolar plasminogen activator activity may reduce fibrosis by removing the provisional fibrin matrix or by increased levels of matrix metalloproteinases (MMPs). To test this hypothesis, 3 models of enhanced alveolar plasminogen activator activity will be employed. These models include a PAI-1 deficient transgenic mouse, adenoviral-mediated gene transfer of the uPA cDNA to the alveolar space, and an inducible lung-specific uPA expressing transgenic mouse. In addition, to investigate the importance of fibrin in lung scarring, a fibrinogen deficient transgenic mouse will be employed. With these models, differences in fibrin accumulation and MMP activation in mice protected from fibrosis will be compared to susceptible controls. The opportunities provided by the training program will provide the foundation for career advancement and hopefully lead to new therapies for fibrotic lung diseases.
