Thrombin-activatable fibrinolysis inhibitor deficiency attenuates bleomycin-induced lung fibrosis.
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-beta1, 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.
Institute of Clinical Medicine and Biomedical Sciences, Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu-city, Mie 514-8507, Japan.
Hajime
H
Fujimoto
Esteban C
EC
Gabazza
Osamu
O
Taguchi
Yoichi
Y
Nishii
Hiroki
H
Nakahara
Nelson E
NE
Bruno
Corina N
CN
D'Alessandro-Gabazza
Michael
M
Kasper
Yutaka
Y
Yano
Mariko
M
Nagashima
John
J
Morser
George J
GJ
Broze
Koji
K
Suzuki
Yukihiko
Y
Adachi
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D001761:Bleomycin; D001794:Blood Pressure; D001831:Body Temperature; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D025901:Carboxypeptidase B2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D006133:Growth Substances / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010196:Pancreatic Elastase / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
D016207:Cytokines; D006133:Growth Substances; C046193:antithrombin III-protease complex; D001761:Bleomycin; D000990:Antithrombin III; D005337:Fibrin; D005340:Fibrinogen; D003094:Collagen; D009195:Peroxidase; D010447:Peptide Hydrolases; D025901:Carboxypeptidase B2; D010196:Pancreatic Elastase; D006909:Hydroxyproline