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Articles in PresS, published online ahead of print August 2, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00049.2002
Submitted on February 4, 2002
Accepted on July 28, 2002
1 Department of Internal Medicine-Pulmonary, University of Michigan School of Medicine, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: tsisson{at}umich.edu.
Plasminogen activator inhibitor-1 (PAI-1) deficient transgenic mice have improved survival and less fibrosis following intra-tracheal bleomycin instillation. We hypothesize that PAI-1 deficiency limits scarring through unopposed plasminogen activation. If this is indeed true, then we would expect increased urokinase-type plasminogen activator (uPA) expression to result in a similar reduction in scarring and improvement in mortality. To test our hypothesis, using the tetracycline gene regulatory system, we have generated a transgenic mouse model with the features of inducible, lung-specific uPA production. Following doxycycline administration, these transgenic animals expressed increased levels of uPA in their BAL fluid that accelerated intra-pulmonary fibrin clearance. Importantly, this increased plasminogen activator production led to a reduction in both lung collagen accumulation and mortality following bleomycin-induced injury. These results suggest that PAI-1 deficiency does protect against the effects of bleomycin-induced lung injury through unopposed plasmin generation. By allowing the manipulation of plasminogen activation at different phases of the fibrotic process, this model will serve as a powerful tool in further investigations into the pathogenesis of pulmonary fibrosis.
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