CHANGES IN PROCOAGULANT AND FIBRINOLYTIC GENE-EXPRESSION DURING BLEOMYCIN-INDUCED LUNG INJURY IN THE MOUSE

Bleomycin-induced lung injury is an established murine model of human pulmonary fibrosis, Although procoagulant molecules (e.g., tissue fact or [TF]) and fibrinolytic components (e.g., urokinase [u-PA] and type 1 plasminogen activator inhibitor [PAI-1]) have been detected in alveo lar fluid from injured lungs, the origin of these molecules remains un known, We therefore examined the expression of procoagulant and fibrin olytic components in relation to the distribution of parenchymal fibri n in bleomycin-injured lungs, Extravascular fibrin localized to the al veolar and extracellular matrix in injured lung tissue, Injured lung t issue extracts contained elevated levels of PAI-1 activity and decreas ed levels of u-PA activity, Whole lung PAI-1 and TP mRNAs were dramati cally induced by lung injury, In situ hybridization of injured lungs r evealed that PAI-1, u-PA, and TF mRNAs were induced within the fibrin- rich fibroproliferative lesions, primarily in fibroblast-like and macr ophagelike cells, respectively, while TF mRNA was also induced in peri lesional alveolar cells, Taken together, these observations suggest th at the induction of PAI-1 and TF gene expression plays an important ro le in the formation and persistence of extracellular fibrin in bleomyc in injured murine lungs.