Factor XIII cross-links fibrin(ogen) independent of fibrin polymerization in experimental acute liver injury
Factor XIII cross-links fibrin(ogen) independent of fibrin polymerization in experimental acute liver injury
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DOI：
10.1182/blood.2020007415
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发表时间：
2021-05-06
期刊：
影响因子：
20.3
通讯作者：
Luyendyk, James P.
中科院分区：
文献类型：
--
作者：
Poole, Lauren G.;Kopec, Anna K.;Luyendyk, James P.
血管内纤维蛋白凝块的形成遵循一系列有序的反应，这些反应由凝血酶裂解纤维蛋白原催化，导致纤维蛋白聚合并通过因子 XIIIa (FXIIIa) 交联。在受伤组织中观察到血管外纤维蛋白（原）沉积；然而，在这种情况下调节纤维蛋白（原）聚合和交联的机制尚不清楚。本研究的目的是确定对乙酰氨基酚 (APAP) 过量引起的急性肝损伤中纤维蛋白聚合和交联的机制。在野生型小鼠、缺乏 FXIII 催化亚基 (FXIII-/-) 的小鼠和 Fib(AEK) 小鼠中测量 APAP 过量后的肝纤维蛋白（原）沉积和交联，这些小鼠表达对凝血酶介导的纤维蛋白聚合物形成不敏感的突变纤维蛋白原。 APAP 攻击的野生型和 FXIII-/- 小鼠中的肝纤维蛋白（原）沉积相似，但肝纤维蛋白（原）的交联因 FXIII 缺乏而显着减少（> 90％）。令人惊讶的是，在 APAP 攻击的 FibAEK 小鼠中，肝纤维蛋白（原）沉积和交联仅略有减少，这表明在 APAP 损伤的肝纤维蛋白聚合中，交联纤维蛋白（原）的血管外沉积并不严格需要。我们假设受损肝脏中含有高水平反应介质（例如过氧亚硝酸盐）的氧化环境会改变纤维蛋白（原），从而使纤维蛋白聚合受损而不影响 FXIII 介导的交联。值得注意的是，在 APAP 损伤的肝脏中发现了用 3-硝基酪氨酸加合物修饰的纤维蛋白（原）。在生化测定中，过氧亚硝酸盐以浓度依赖性方式抑制凝血酶介导的纤维蛋白聚合，而不影响纤维蛋白（原）随时间的交联。这些研究描绘了一种独特的病理学，其中凝血酶催化的纤维蛋白聚合被规避以允许组织沉积和 FXIII 依赖性纤维蛋白（原）交联。
Intravascular fibrin clot formation follows a well-ordered series of reactions catalyzed by thrombin cleavage of fibrinogen leading to fibrin polymerization and cross-linking by factor XIIIa (FXIIIa). Extravascular fibrin(ogen) deposits are observed in injured tissues; however, the mechanisms regulating fibrin(ogen) polymerization and cross-linking in this setting are unclear. The objective of this study was to determine the mechanisms of fibrin polymerization and cross-linking in acute liver injury induced by acetaminophen (APAP) overdose. Hepatic fibrin(ogen) deposition and cross-linking were measured following APAP overdose in wild-type mice, mice lacking the catalytic subunit of FXIII (FXIII-/-), and in Fib(AEK) mice, which express mutant fibrinogen insensitive to thrombin-mediated fibrin polymer formation. Hepatic fibrin(ogen) deposition was similar in APAP-challenged wildtype and FXIII-/- mice, yet cross-linking of hepatic fibrin(ogen) was dramatically reduced (>90%) by FXIII deficiency. Surprisingly, hepatic fibrin(ogen) deposition and cross-linking were only modestly reduced in APAP-challenged FibAEK mice, suggesting that in the APAP-injured liver fibrin polymerization is not strictly required for the extravascular deposition of cross-linked fibrin(ogen). We hypothesized that the oxidative environment in the injured liver, containing high levels of reactive mediators (eg, peroxynitrite), modifies fibrin(ogen) such that fibrin polymerization is impaired without impacting FXIII-mediated cross-linking. Notably, fibrin(ogen) modified with 3-nitrotyrosine adducts was identified in the APAP-injured liver. In biochemical assays, peroxynitrite inhibited thrombin-mediated fibrin polymerization in a concentration-dependent manner without affecting fibrin(ogen) cross-linking over time. These studies depict a unique pathology wherein thrombin-catalyzed fibrin polymerization is circumvented to allow tissue deposition and FXIII-dependent fibrin(ogen) cross-linking.