The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis
The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis
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DOI：
10.1172/jci200318114
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发表时间：
2003-07-01
影响因子：
15.9
通讯作者：
Levy, GA
中科院分区：
文献类型：
--
作者：
Marsden, PA;Ning, Q;Levy, GA
现在人们认识到，微血管内的纤维蛋白沉积和血栓形成在实验性和人类病毒性肝炎中观察到的肝细胞损伤中发挥着关键作用。重要的是，病毒性肝炎中引发纤维蛋白生成的途径可能在机制上不同于机械创伤或细菌脂多糖（LPS）诱导的凝血的经典途径。在鼠肝炎病毒 3 株 (MHV-3)（冠状病毒科成员）感染的情况下，活化的内皮细胞和巨噬细胞表达不同的细胞表面促凝血剂，包括一种新型凝血酶原酶 Fgl2/纤维白介素，它对于纤维蛋白沉积的启动和定位都很重要。为了评估 Fgl2/纤维白介素在鼠病毒性肝炎中的作用，我们制备了 Fgl2/纤维白介素缺陷的小鼠。当感染MHV-3时，从Fgl2/纤维白介素(-/-)小鼠中分离的腹膜巨噬细胞不产生促凝血反应。感染 MHV-3 的小鼠的纤维蛋白沉积和肝坏死显着减少，存活率增加。为了解决 Fgl2/ 纤维白介素在人类慢性病毒性肝炎中的相关性，我们研究了轻度和明显慢性乙型肝炎患者。我们在从明显慢性乙型肝炎患者分离的肝组织中检测到 Fgl2/纤维白介素 mRNA 转录物和蛋白质的强烈表达。纤维蛋白沉积与 Fgl2/纤维白介素表达密切相关。总的来说，这些数据表明 Fgl2/纤维白介素在实验性和人类病毒性肝炎的病理生理学中发挥着关键作用。
Fibrin deposition and thrombosis within the microvasculature is now appreciated to play a pivotal role in the hepatocellular injury observed in experimental and human viral hepatitis. Importantly, the pathways by which fibrin generation is elicited in viral hepatitis may be mechanistically distinct from the classical pathways of coagulation induced by mechanical trauma or bacterial lipopolysaccharide (LPS). In the setting of murine hepatitis virus strain-3 (MHV-3) infection, a member of the Coronaviridae, activated endothelial cells and macrophages express distinct cell-surface procoagulants, including a novel prothrombinase, Fgl2/fibroleukin, which are important for both the initiation and localization of fibrin deposition. To assess the role of Fgl2/fibroleukin in murine viral hepatitis we generated a Fgl2/fibroleukin-deficient mouse. Peritoneal macrophages isolated from Fgl2/fibroleukin(-/-) mice did not generate a procoagulant response when infected with MHV-3. Fibrin deposition and liver necrosis were markedly reduced, and survival was increased in mice infected with MHV-3. To address the relevance of Fgl2/fibroleukin in human chronic viral hepatitis we studied patients with minimal and marked chronic hepatitis B. We detected robust expression of Fgl2/fibroleukin mRNA transcripts and protein in liver tissue isolated from patients with marked chronic hepatitis B. Fibrin deposition was strongly associated with Fgl2/fibroleukin expression. Collectively, these data indicate a critical role for Fgl2/fibroleukin in the pathophysiology of experimental and human viral hepatitis.