thrombin-activatable fibrinolysis inhibitor deficiency attenuates bleomycin-induced lung fibrosis
thrombin-activatable fibrinolysis inhibitor deficiency attenuates bleomycin-induced lung fibrosis
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DOI：
10.2353/ajpath.2006.050610
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发表时间：
2006-04-01
影响因子：
6
通讯作者：
Adachi, Y
中科院分区：
文献类型：
--
作者：
Fujimoto, H;Gabazza, EC;Adachi, Y
纤溶功能降低有利于肺纤维化的发展。凝血酶激活的纤溶抑制物(TAFI)是一种强烈的纤溶抑制物，但其在肺纤维化中的作用尚不清楚。因此，我们比较了TAFI缺陷型、杂合型和野生型小鼠中博莱霉素诱导的肺纤维化。给药21d后处死动物，测定肺纤维化和炎症指标。与野生型小鼠相比，基因敲除小鼠肺泡灌洗液中总蛋白、中性粒细胞蛋白酶(弹性蛋白酶、髓过氧化物酶)、细胞因子(肿瘤坏死因子-α、白介素13)、趋化因子(单核细胞趋化蛋白-1)、凝血酶-抗凝血酶复合体、总可溶性胶原、生长因子(血小板衍生生长因子、转化生长因子-α、粒细胞-巨噬细胞生长因子)水平显著降低。此外，与野生型小鼠相比，基因敲除小鼠肺组织纤维化、纤维蛋白沉积、羟脯氨酸和胶原含量显著减少。在基因敲除和野生型小鼠中，通过ANCORD治疗耗尽纤维蛋白原导致肺纤维化和胶原沉积的数量相等。不同表型的小鼠在体温或动脉压方面没有发现差异。这些结果表明，TAFI的抗纤溶活性通过抑制纤维蛋白的降解速度促进了肺纤维化。
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, interlleukin-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-alpha, 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.