LPS/D-gal诱导急性肝衰竭小鼠肝组织cGAS-STING通路蛋白表达及其肝素保护作用研究

doi:10.3969/j.issn.1672-5069.2026.05.003

摘要/Abstract

摘要： 目的探讨胞外组蛋白和肝素干预对脂多糖(LPS)联合D-氨基半乳糖(D-gal)诱导的急性肝衰竭(ALF)小鼠肝组织环鸟苷酸-腺苷酸合成酶(cGAS)-干扰素刺激因子(STING)通路蛋白表达的影响。方法将40只小鼠随机分为对照组、模型组、胞外组蛋白干预组和胞外组蛋白联合肝素干预组,每组10只,采用LPS联合D-gal 腹腔注射建立ALF模型,采用Western blot法检测肝组织cGAS和STING蛋白表达,采用Elisa法检测肝组织匀浆肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-1β和IL-18水平。结果肝组织病理学检查显示,ALF模型制备成功;胞外组蛋白干预组肝组织损害与模型组表现相似,而胞外组蛋白联合肝素干预组肝组织损害较轻;模型组和胞外组蛋白干预组血清ALT和AST水平显著高于对照组(P<0.05),而胞外组蛋白联合肝素干预组血清ALT和AST水平较模型组和胞外组蛋白干预组均显著降低(P<0.05);模型组和胞外组蛋白干预组小鼠肝组织cGAS和STING表达及TNF-α、IL-1β和IL-18水平均较对照组显著增强或升高,而胞外组蛋白联合肝素干预组肝组织cGAS和STING表达及TNF-α、IL-1β和IL-18水平均较模型组和胞外组蛋白干预组显著减弱或降低(P<0.05)。结论胞外组蛋白能够通过激活cGAS-STING通路诱发急性肝损伤,而肝素可能通过抑制胞外组蛋白表达,阻断cGAS-STING通路而发挥保护作用。

关键词: 急性肝衰竭, 胞外组蛋白, 肝素, 环鸟苷酸-腺苷酸合成酶-干扰素刺激因子通路, 小鼠

Abstract: Objective This experiment aimed to investigate the effects of extracellular histones and heparin intervention on cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in mice with lipopolysaccharide (LPS)/D-galactosamine(D-gal)-induced acute liver failure (ALF). Methods Forty mice were randomly divided into control, model, extracellular histones -intervened and extracellular histones/ heparin-intervened groups , with 10 mice in each. ALF model was established in mice by using LPS/D-gal intraperitoneal injection. Hepatic protein expression of cGAS and STING were detected by Western blotting, and hepatic homogenate tumor necrosis factor-α(TNF-α),interleukin ( IL)-1β and IL-18 levers were measured by using ELISA. Results Histopathological examination of liver tissue confirmed the successful establishment of ALF model in mice, liver tissue damage in the extracellular histones-intervened group was similar to that in the model group, whereas it was significantly milder in the extracellular histones/heparin-intervened group; serum ALT and AST levels in the model group and extracellular histones group were significantly higher than those in the control group (P<0.05), while they decreased greatly in the extracellular histones/heparin-intervened group (P<0.05); hepatic cGAS and STING expression, and liver tissue homogenate TNF-α, IL-1β and IL-18 levels in the model group and extracellular histones group were significantly intensified and elevated as compared to in the control group (P<0.05), however,the expression or levels of these molecules in the extracellular histones/heparin group were significantly weaken or reduced compared to both in the model group or in the extracellular histones group (P<0.05). Conclusion Extracellular histones could induce ALF, probably by activating the cGAS-STING pathway,while heparin might inhibit extracellular histone expression and block the cGAS-STING pathway and thereby exerting a protective effect.

Key words: Acute liver failure, Extracellular histone, Heparin, cyclic GMP-AMP synthase- stimulator of interferon genes, Mice

罗轲, 张丹眉, 郭金, 龚作炯. LPS/D-gal诱导急性肝衰竭小鼠肝组织cGAS-STING通路蛋白表达及其肝素保护作用研究[J]. 实用肝脏病杂志, 2026, 29(5): 649-652.

Luo Ke, Zhang Danmei, Guo Jin, et al. Hepatic tissue of cGAS-STING pathway proteins and heparin’s protective roles in LPS/D-gal-induced acute liver failure in mice[J]. Journal of Practical Hepatology, 2026, 29(5): 649-652.

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