Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice.
Plasminogen activator inhibitor-1 (PAI-1)-deficient transgenic mice have improved survival and less fibrosis after intratracheal 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. After doxycycline administration, these transgenic animals expressed increased levels of uPA in their bronchoalveolar lavage (BAL) fluid that accelerated intrapulmonary fibrin clearance. Importantly, this increased plasminogen activator production led to a reduction in both lung collagen accumulation and mortality after 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.
Sisson
Thomas H
TH
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. tsisson@umich.edu
Hanson
Kerstin E
KE
Subbotina
Natalya
N
Patwardhan
Anjali
A
Hattori
Noboru
N
Simon
Richard H
RH
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005838:Genotype; D006801:Humans; D008168:Lung / Q000473:pathology; D055370:Lung Injury; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
D017931:DNA Primers; D014568:Urokinase-Type Plasminogen Activator