血栓调节蛋白可改善实验性热射病模型中小鼠的肝损伤、凝血功能障碍和死亡率。

Thrombomodulin improved liver injury, coagulopathy, and mortality in an experimental heatstroke model in mice.

机构信息

From the Department of Anesthesiology, University of Occupational and Environmental Health, Kitakyushu, Japan.

出版信息

Anesth Analg. 2014 May;118(5):956-63. doi: 10.1213/ANE.0000000000000170.

DOI:10.1213/ANE.0000000000000170

PMID:24781566

Abstract

BACKGROUND

Heatstroke is a life-threatening illness and causes high mortality due to multiple organ injuries. Thrombomodulin (TM) is an endothelial anticoagulant cofactor that plays an important role in the regulation of intravascular coagulation. In this study, we investigated the effect of TM on the inflammatory process, liver function, coagulation status, and mortality in experimental heatstroke.

METHODS

Male C3H/HeN (8-10 weeks) mice were randomly assigned to the TM-treated group (TG-Pre) or nontreated heatstroke group (HS). In group TG-Pre, mice were treated with recombinant soluble TM (1 mg/kg, intraperitoneally) before heat exposure. In some experiments, recombinant soluble TM was administrated during heat exposure (TG-Delay). Heatstroke was induced by exposure to ambient temperature of 38°C for 4 hours. After heat exposure, the levels of tumor necrosis factor-α, interleukin-6, and plasma high-mobility group box 1 (HMGB1), liver function, plasma aspartate aminotransferase and alanine aminotransferase concentrations, and immunohistochemical and histopathological characteristics of the livers were determined. The coagulation status, plasma protein C levels, and thrombin-antithrombin complex levels were also measured.

RESULTS

In group HS, plasma cytokines and HMGB1 concentrations increased after heat exposure. Plasma aspartate aminotransferase and alanine aminotransferase concentrations increased after heat exposure. In group HS livers, strong and extensive immunostaining for HMGB1 was observed. In addition, there was extensive hepatocellular necrosis and collapse of nuclei observed. In group HS, plasma protein C levels were suppressed and plasma thrombin-antithrombin complex levels increased. In group TG-Pre, plasma cytokines and HMGB1 concentrations were suppressed after heat exposure compared with group HS. Liver injury, coagulopathy, and mortality also improved in group TG-Pre. Furthermore, recombinant soluble TM treatment decreased mortality even with delayed treatment.

CONCLUSIONS

This study demonstrated that recombinant soluble TM suppressed plasma cytokines and HMGB1 concentrations after heat exposure. Recombinant soluble TM also improved liver injury and coagulopathy. Recombinant soluble TM treatment improved mortality even with delayed treatment. Recombinant soluble TM may be a beneficial treatment for heatstroke patients.

摘要

背景

中暑是一种危及生命的疾病，会导致多器官损伤，死亡率很高。血栓调节蛋白（TM）是一种内皮抗凝辅助因子，在调节血管内凝血中起重要作用。在这项研究中，我们研究了 TM 对实验性中暑中炎症过程、肝功能、凝血状态和死亡率的影响。

方法

雄性 C3H/HeN（8-10 周）小鼠被随机分配到 TM 治疗组（TG-Pre）或未治疗的中暑组（HS）。在 TG-Pre 组中，在暴露于热之前，用重组可溶性 TM（1mg/kg，腹腔内）处理小鼠。在一些实验中，在暴露于热期间给予重组可溶性 TM（TG-Delay）。通过将环境温度暴露于 38°C 4 小时来诱导中暑。暴露于热后，测定肿瘤坏死因子-α、白细胞介素-6 和血浆高迁移率族蛋白 1（HMGB1）水平、肝功能、血浆天冬氨酸转氨酶和丙氨酸转氨酶浓度以及肝脏的免疫组织化学和组织病理学特征。还测量了凝血状态、血浆蛋白 C 水平和凝血酶-抗凝血酶复合物水平。

结果

在 HS 组中，暴露于热后血浆细胞因子和 HMGB1 浓度增加。暴露于热后血浆天冬氨酸转氨酶和丙氨酸转氨酶浓度增加。在 HS 组肝脏中，观察到 HMGB1 的强烈和广泛免疫染色。此外，还观察到广泛的肝细胞坏死和细胞核塌陷。在 HS 组中，血浆蛋白 C 水平受到抑制，血浆凝血酶-抗凝血酶复合物水平升高。在 TG-Pre 组中，与 HS 组相比，暴露于热后血浆细胞因子和 HMGB1 浓度降低。TG-Pre 组的肝损伤、凝血障碍和死亡率也得到改善。此外，即使延迟治疗，重组可溶性 TM 治疗也降低了死亡率。