目的 探究Janus激酶1(JAK1)抑制剂伊他替尼(ITA)治疗小鼠自身免疫性肝炎(AIH)的效果。方法 将30只雄性BALB/c小鼠随机分为空白对照组、模型组和ITA组,每组10只。模型组和ITA组小鼠通过尾静脉注射刀豆蛋白A(Con A)25 mg/kg建立AIH模型,空白对照组注射等量生理盐水。造模30 min后,ITA组腹腔给予伊他替尼(10 mg/kg),空白对照组和模型组给予等量生理盐水。Con A注射8 h后处死小鼠,采集血清及肝组织样本。采用HE染色观察肝组织病理学变化,分别测定血清肝功能指标、炎症因子水平和肝组织CD3+ T细胞、CD4+ T细胞浸润比例。结果 与空白对照组相比,模型组小鼠肝脏出现明显肿大、充血及点状出血灶,肝小叶结构紊乱并伴有大面积肝细胞坏死;血清ALT、AST水平及TNF-α、IL-6、IL-2含量均升高;肝组织内CD3+ T细胞及CD4+ T细胞浸润比例也增加(均P<0.05),差异具有统计学意义。与模型组相比,ITA组小鼠肝脏外观及病理结构明显改善,肝损伤区域减小;血清ALT和AST水平及TNF-α、IL-6及IL-2水平均下降;肝组织中CD3+ T细胞及CD4+ T细胞浸润比例亦减少(均P<0.05),差异具有统计学意义。结论 ITA能有效减轻Con A诱导的AIH小鼠肝损伤,其机制可能与抑制JAK1信号通路,从而减少T淋巴细胞浸润及炎症因子(TNF-α、IL-6、IL-2)的释放有关。
Abstract
Objective To investigate the therapeutic efficacy of Janus kinase 1 (JAK1) inhibitor of Itacitinib (ITA) on autoimmune hepatitis (AIH) in mice. Methods A total of 30 male BALB/c mice were randomly divided into three groups with 10 mice in each group: a blank control group, a model group, and an ITA group. AIH models were established by tail vein injection of concanavalin A (Con A) at a dose of 25 mg/kg in the model and ITA groups, while the control group received an equal volume of normal saline. Thirty minutes after modeling, the ITA group was intraperitoneally administered ITA (10 mg/kg), whereas the control and model groups received an equal volume of saline. All mice were euthanized for 8 hours after the Con A injection, and serum and liver tissue samples were collected. Histopathological changes in liver tissues were observed using HE staining, and serum levels of liver function markers, inflammatory cytokines, as well as the infiltration proportions of CD3+ T cells and CD4+ T cells in liver tissue were measured. Results Compared with the blank control group, the model group exhibited significant liver enlargement, congestion, and spotted hemorrhages, disordered hepatic lobule structure and extensive hepatocellular necrosis; serum levels of ALT and AST, as well as TNF-α, IL-6, and IL-2 concentrations were significantly elevated; infiltration proportions of both CD3+ T cells and CD4+ T cells in the liver tissues also increased (P<0.05), indicating statistically significant differences. Compared with the model group, the ITA group showed obvious improvements in liver appearance and pathological structure, with reduced areas of liver damage, decreased serum ALT and AST levels and lower levels of TNF-α and IL-6; infiltration ratios of CD3+ T cells and CD4+ T cells in the liver tissue were also reduced (all P< 0.05), showing statistically significant differences. Conclusions ITA can effectively alleviate liver damage in Con A-induced AIH mice, possibly through inhibition of the JAK1 signaling pathway, thereby reducing T lymphocyte infiltration and the release of inflammatory cytokines(TNF-α, IL-6, and IL-2).
关键词
JAK1抑制剂 /
自身免疫性肝炎 /
伊他替尼 /
刀豆蛋白A /
炎症细胞因子
Key words
JAK1 inhibitor /
autoimmune hepatitis /
Itacitinib /
concanavalin a /
inflammatory cytokines
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