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

炎症反应介导的高凝是伴刀豆球蛋白 A 诱导小鼠严重肝炎的基础

基本信息

批准号：
22659328
负责人：
TSUTSUI Hiroko
金额：
$ 2.11万
依托单位：
Hyogo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Challenging Exploratory Research
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22659328/
关键词：
集中治療医学劇症肝炎 Concanavalin A DIC TAT 組織因子炎症性サイトカイン IFNγ TNF 異常凝固亢進組織因子UTissue Factor PAI-1 フィブリン沈着 Con A

项目摘要

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.

刀豆蛋白A诱导小鼠重型肝炎的方式依赖于T细胞、干扰素γ和肿瘤坏死因子。尽管干扰素、γ和肿瘤坏死因子的产生正常，但抗凝剂肝素的治疗可以预防肝炎。在这里，我们研究了高凝状态下肝炎的分子和细胞机制。ConA攻击后，野生型小鼠肝脏迅速产生干扰素γ和肿瘤坏死因子，随后出现组织因子(Tf)的表达，从而启动凝血。小鼠出现致密的肝内纤维蛋白沉积和大量肝坏死。相反，干扰素γ-/-小鼠和干扰素γ-/-肿瘤坏死因子-/-小鼠既没有诱发转铁蛋白，也没有发生肝炎。在野生型小鼠中，用抗Tf抗体阻断Tf对ConA诱导的肝炎具有保护作用。ConA刺激后，肝巨噬细胞和肝窦内皮细胞均表达TF。用造血细胞(包括干扰素γ信号转导所必需的STAT1缺失的巨噬细胞)重组的去巨噬细胞野生型小鼠，肝组织转铁蛋白显著降低，肝损伤明显减轻。用野生型巨噬细胞重组的巨噬细胞耗尽的STAT1-/-小鼠也是如此。外源性干扰素γ和肿瘤坏死因子使T细胞缺失、ConA耐药、重组激活基因2缺失的小鼠对ConA诱导的肝损伤高度敏感，涉及Tf。总之，这些结果有力地表明，干扰素γ、肿瘤坏死因子和刀豆蛋白A在肝巨噬细胞和肝窦内皮细胞中诱导的促炎信号在高凝介导的肝炎的发生发展中是必要的和充分的。