Inflammatory response-mediated Hypercoagulation underlies Concanavalin A-induced severe hepatitis in mice

Con A处理以依赖于T细胞、IFNγ和TNF的方式在小鼠中诱导重度肝炎。尽管IFNγ和TNF的产生正常，但抗凝肝素治疗可预防肝炎。在这里，我们研究了高凝介导的肝炎的分子和细胞机制。ConA刺激后，野生型小鼠肝脏出现Ifnγ和Tnf的迅速诱导，随后组织因子（TF）的mRNA表达，启动血液凝固。小鼠出现密集的肝内纤维蛋白沉积和大面积肝坏死。相反，Ifnγ-/-小鼠和Ifnγ-/-Tnf-/-小鼠既不诱导Tf，也不发生肝炎。在野生型小鼠中，用抗TF抗体阻断TF可防止Con A诱导的肝炎。ConA刺激后肝巨噬细胞和窦状隙内皮细胞均表达Tf。用造血细胞（包括缺乏IFNγ信号传导所必需的STAT 1的巨噬细胞）重建的巨噬细胞耗竭野生型小鼠显示肝Tf和肝损伤显著降低。对于用野生型巨噬细胞重建的巨噬细胞缺失的Stat 1-/-小鼠来说也是如此。外源性IFNγ和TNF使T细胞缺失、ConA抗性小鼠重组激活基因2缺陷，对涉及TF的ConA诱导的肝损伤高度敏感。总的来说，这些结果强烈表明，在肝巨噬细胞和窦内皮细胞中由IFNγ、TNF和Con A引起的促炎信号对于高凝介导的肝炎的发展是必要的和充分的。

Con A treatment induces severe hepatitis in mice in a manner dependent on T cells, IFNγ and TNF. Treatment with the anticoagulant heparin protects against hepatitis despite normal production of IFNγ and TNF. Here, we investigated molecular and cellular mechanisms for hypercoagulation-mediated hepatitis. After Con A challenge liver of wild-type mice showed prompt induction of Ifnγ and Tnf, followed by mRNA expression of tissue factor(TF), which initiate blood coagulation. The mice developed dense intrahepatic fibrin deposition and massive liver necrosis. In contrast, Ifnγ-/-mice and Ifnγ-/-Tnf-/-mice neither induced Tf, nor developed hepatitis. In wild-type mice TF blockade with an anti-TF antibody protected against Con A-induced hepatitis. Both hepatic macrophages and sinusoidal endothelial cells expressed Tf after Con A challenge. Macrophage-depleted wild-type mice reconstituted with hematopoietic cells including macrophages deficient in STAT1 essential for IFNγ signaling, exhibited substantial reduction of hepatic Tf and of liver injuries. This was also true for macrophage-depleted Stat1-/-mice reconstituted with wild-type macrophages. Exogenous IFNγ and TNF rendered T cell-null, Con A-resistant mice deficient in recombination-activating gene 2, highly susceptible to Con A-induced liver injury involving TF. Collectively, these results strongly suggested that pro-inflammatory signals elicited by IFNγ, TNF and Con A in both hepatic macrophages and sinusoidal endothelial cells are necessary and sufficient for the development of hypercoagulation-mediated hepatitis.