Intratracheal administration of activated protein C inhibits bleomycin-induced lung fibrosis in the mouse

It is well recognized that activation of the coagulation system plays an im portant role in bleomycin (BLM)-induced lung injury and fibrosis. The prote in C (PC) pathway is an important regulator of the coagulation system. In t his study, we evaluated the bronchoalveolar lavage fluid (BALF) concentrati on of activated PC (APC) and the therapeutic effect of the intratracheal ad ministration of APC on BLM-induced lung fibrosis in mice. APC revels in BAL F were significantly lower in BLM-treated animals than in the saline-treate d group. Fibrotic changes were progressive in mice treated with BLM and int ratracheal instillation of vehicle (BLM/Veh) after 14 and 21 d of BLM infus ion. Compared with the BLM/Veh group, histologic findings on Days 14 and 21 in mice treated with BLM and intratracheal instillation of APC (BLM/APC) s howed less fibrotic lesions in the subpleural and central areas of the lung . The mean Aschcroft's fibrosis score in the BLM/Veh group was significantl y (p < 0.05) higher than in the BLM/APC group. The lung hydroxyproline cont ent on Day 21 was significantly higher (p < 0.05) in the BLM/Veh group (1.7 8 +/- 0.07 mu mol/lung weight) than in the BLM/APC (1.30 +/- 0.06 mu mol/lu ng weight) group. The ratio of plasminogen activator activity to thrombin l evel in BALF was significantly increased in the BLM/APC group compared with the BLM/Veh group on Day 21. The expression of tumor necrosis factor-alpha and interleukin-1 beta was significantly decreased in the lungs of the BLM /APC group compared with the BLM/Veh group on Day 14 after BLM infusion. Th ese results showed that intratracheal APC administration inhibits the devel opment of lung fibrosis in BLM-induced lung injury, giving further support to the important role that the PC pathway plays in the mechanism of lung fi brosis.