| Research Abstract |
We have previously demonstrated that plasminogen activator inhibitor-1 (PAl-1) deficient (PAl-1-/-) mice are protected from developing bleomycin-induced pulmonary fibrosis. We hypothesize that PAl-1 deficiency limits fibrosis through enhanced fibrinolytic activity. Using the tetracycline gene regulatory system, we have generated a transgenic mouse model with the features of inducible, lung specific urokinase. expression. After doxycycline administration, these transgenic mice showed enhanced fibrinolytic activity in the lung and were protected from developing bleomycin-induced pulmonary fibrosis. While searching for an alternative mechanism by which the fibrinolytic system limits pulmonary fibrosis, we have developed an interest in hepatocyte growth factor (HGF). This growth factor, when administered systemically or intratracheally, attenuates bleomycin-induced pulmonary fibrosis, and its activation is in part mediated by the fibrinolytic system. In the current study, we found that HGF
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levels in BAL fluids following bleomycin administration were significantly higher in PAl-1-/-mice compared to PAl-1+/+ mice. Treatment of the bleomycin-injured mice with tranexamic acid, an inhibitor of fibrinolytic system, decreased HGF levels in the bronchoalveolar lavage (BAL) fluids. In addition, neutralization of endogenous HGF in bleomycin-injured PAl-1-/-mice with an anti-HGF antibody markedly increased collagen accumulation in the lungs. Furthermore, we demonstrated that the intratracheal instillation of urokinase into bleomycin-injured PAl-1+/+ mice resulted in a significant increase in the BAL HGF level and less collagen accumulation in the lungs. These results suggest that a mechanism by which the fibrinolytic system limits pulmonary fibrosis is through the mediation of HGF.
Based on these results, we tried aerosol delivery of urokinase to bleomycin-injured mice lungs but found that this approach could not protect the lungs from developing pulmonary fibrosis. This could be due to low efficiency of aerosol delivery to mice lungs. Improvement of aerosol delivery system and alteration of animal models should be considered. Less
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