Treatment of bleomycin-induced pulmonary fibrosis by transfer of urokinase-type plasminogen activator genes

During acute and chronic inflammatory lung diseases, the normal fibrinolyti c activity in the alveolar space is inhibited by increased levels of plasmi nogen activator inhibitor 1 (PAI-1), Transgenic mice having increased fibri nolytic activity due to genetic deficiency of PAI-1 develop less fibrosis a fter bleomycin-induced lung inflammation. These observations led us to hypo thesize that pulmonary fibrosis could be limited through enhancement of alv eolar fibrinolytic activity by adenovirus-mediated transfer of the urokinas e-type plasminogen activator (uPA) gene to the lung. To investigate this hy pothesis, 0.075 U of bleomycin was introduced intratracheally into mice. Tw enty-one days later, the mice were treated intratracheally with phosphate-b uffered saline (PBS), a control adenovirus, or adenoviruses containing muri ne or human uPA cDNAs. On day 28, the mice were sacrificed, and lung fibros is was quantitated by measuring hydroxyproline content, As expected, bleomy cin caused a doubling in lung hydroxyproline to 345.6 +/- 28.2 mu g/lung (S EM) compared with mice receiving PBS (170.2 +/- 4.0 mu g/lung). Treatment o f the bleomycin-injured mice with the control adenovirus on day 21 had no i mpact on lung fibrosis (338.4 +/- 17.2 mu g/lung). Importantly, the human u PA adenovirus significantly reduced (p < 0.05) lung hydroxyproline (281.2 /- 22.8 mu g/lung), thus attenuating by 38% the bleomycin-induced increase in lung collagen. The improvement in bleomycin-induced lung fibrosis result ing from treatment with the human uPA adenovirus further supports the impor tance of the fibrinolytic system during inflammatory lung injury and repair .