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

Abstract

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-␣, 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-␤1, granulocytic-macrophage growth factor) were significantly decreased in knockout mice compared to wildtype 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.

Curiouser and curiouser: Recent advances in measurement of thrombin-activatable fibrinolysis inhibitor (TAFI) and in understanding its molecular genetics, gene regulation, and biological roles

“…Recently, accelerated endogenous fibrinolysis has been observed in the TAFI −/− mice, using a batroxobin-induced pulmonary embolism model [86]. These results are in agreement with another report in which TAFI −/− mice exhibited less bleomycin-induced lung fibrosis, potentially reflecting the ability of the TAFI pathway to attenuate local plasmin generation in the lung [87].…”

Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids

“…A 4G/5G polymorphism in the PAI-1 promoter region has been reported, and preferential transmission of the 4G allele correlates with increased PAI-1 expression in asthma 8 32. PAI-1 and TAFI have been implicated in normal wound healing, and increased expression of both PAI-17 8 and TAFI30 33 has also been implicated in fibrin formation leading to the development of lung fibrosis. To our knowledge this is the first report of increased TAFI levels in the asthmatic airway.…”

Assessment of Respiratory Physiology of C57BL/6 Mice following Bleomycin Administration Using Barometric Plethysmography

“…The bleomycin model is easy to establish, robust, reproducible and versatile [6] and was originally developed in dogs [7], then adapted to mice [8,9], hamsters [10], rats [11,12] and rabbits [13,14]. To induce pulmonary fibrosis, bleomycin may be administered by various routes, including intratracheal [15], intranasal [16], intraperitoneal [17] and osmotic mini-pump [18] administration. The type, severity and pattern of parenchymal lesions arising following bleomycin administration are route and dose dependent [6].…”