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(American Journal of Pathology. 2006;168:1086-1096.)
© 2006 American Society for Investigative Pathology

Thrombin-Activatable Fibrinolysis Inhibitor Deficiency Attenuates Bleomycin-Induced Lung Fibrosis

Hajime Fujimoto*, Esteban C. Gabazza*{dagger}, Osamu Taguchi*, Yoichi Nishii*, Hiroki Nakahara*, Nelson E. Bruno*, Corina N. D’Alessandro-Gabazza*, Michael Kasper{ddagger}, Yutaka Yano*, Mariko Nagashima§, John Morser§, George J. Broze, Koji Suzuki{dagger} and Yukihiko Adachi*

From the Departments of Pulmonary and Critical Care Medicine* and Molecular Pathobiology,{dagger} Mie University School of Medicine, Mie, Japan; the Institute of Anatomy,{ddagger} Technical University of Dresden, Dresden, Germany; the Department of Cardiovascular Research,§ Berlex Biosciences, Richmond, California; and the Department of Medicine, Jewish Hospital at Washington University, St. Louis, Missouri

Decreased fibrinolytic function favors the development of pulmonary fibrosis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a strong suppressor of fibrinolysis, but its role in lung fibrosis is unknown. Therefore, we compared bleomycin-induced lung fibrosis in TAFI-deficient, heterozygous, and wild-type mice. The animals were sacrificed 21 days after bleomycin administration, and markers of lung fibrosis and inflammation were measured. The bronchoalveolar lavage fluid levels of total protein, neutrophil proteases (elastase, myeloperoxidase), cytokines (tumor necrosis factor-{alpha}, interleukin-13), chemokine (monocyte chemoattractant protein-1), coagulation activation marker (thrombin-antithrombin complex), total soluble collagen, and growth factors (platelet-derived growth factor, transforming growth factor-ß1, granulocytic-macrophage growth factor) were significantly decreased in knockout mice compared to wild-type mice. Further, histological findings of fibrosis, fibrin deposition, and hydroxyproline and collagen content in the lung were significantly decreased in knockout mice compared to wild-type mice. Depletion of fibrinogen by ancrod treatment led to equalization in the amount of fibrosis and collagen deposition in the lungs of knockout and wild-type mice. No difference was detected in body temperature or arterial pressure between the different mouse phenotypes. These results suggest that the anti-fibrinolytic activity of TAFI promotes lung fibrosis by hindering the rate at which fibrin is degraded.




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