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细胞坏死抑制剂 TAK-632 治疗急性胰腺炎的疗效及分子机制

Efficacy and molecular mechanism of cell necrosis inhibitor TAK-632 in treatment of acute pancreatitis

    摘要
  • 摘要:
      目的  探讨细胞坏死抑制剂TAK-632对急性胰腺炎(AP)的保护作用分子机制。
      方法  将60只SD大鼠随机分为对照组、模型组和TAK-632组, 每组20只。建立AP大鼠模型，建模24 h后，对照组和模型组大鼠经腹腔注射生理盐水, TAK-632组经腹腔注射25 mg/kg TAK-632。治疗72 h后，观察3组大鼠存活率、血清淀粉酶活性、胰腺病理学变化、外周血肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)表达水平以及胰腺组织受体相互作用蛋白3(RIP3)和混合谱系激酶结构区域样蛋白(MLKL)表达水平。
      结果  对照组、模型组、TAK-632组大鼠存活率分别为100.00%、75.00%、100.00%，与对照组和TAK-632组大鼠比较，模型组大鼠存活率下降，差异有统计学意义(P < 0.05)。TAK-632组大鼠血清淀粉酶活性和病理学评分高于对照组，但低于模型组，差异有统计学意义(P < 0.05)。TAK-632组大鼠外周血TNF-α、IL-1β和IL-6表达水平高于对照组，但低于模型组，差异有统计学意义(P < 0.05)。TAK-632组大鼠胰腺组织中磷酸化RIP3和MLKL水平高于对照组，但低于模型组，差异有统计学意义(P < 0.05)。
      结论  TAK-632通过抑制RIP3和MLKL磷酸化抑制炎症因子的释放和减慢细胞坏死进程，从而缓解AP。

     

    Abstract:
      Objective  To investigate the protective effect of cell necrosis inhibitor TAK-632 for acute pancreatitis (AP) and its molecular mechanism.
      Methods  A total of 60 SD rats were randomly divided into control group, model group and TAK-632 group, with 20 rats in each group. The AP rat model was established. After 24 hours of modeling, rats in the control and model groups were injected with saline intraperitoneally, and rats in the TAK-632 group were injected with TAK-632 25 mg/kg intraperitoneally. After 72 hours of treatment, the survival rate, serum amylase activity, pancreatic pathological changes, the expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in peripheral blood, and the expressions of programmed necrosis protein receptor-interacting protein 3(RIP3) and mixed lineage kinase domain-like protein(MLKL) in pancreatic tissue were observed.
      Results  The survival rates of rats in the control group, model group, and TAK-632 group were 100.00%, 75.00% and 100.00%, respectively. Compared with the control group and TAK-632 group, the survival rate of the model group was significantly decreased (P < 0.05). Serum amylase activity and pathological scores of rats in the TAK-632 group were higher than those of the control group, but lower than those of the model group (P < 0.05). The levels of TNF-α, IL-1β and IL-6 in the peripheral blood of rats in the TAK-632 group were higher than those in the control group, but lower than those in the model group (P < 0.05). The levels of phosphorylated RIP3 and MLKL in the pancreatic tissue of rats in the TAK-632 group were higher than those in the control group, but lower than those in the model group (P < 0.05).
      Conclusion  TAK-632 can inhibit the release of inflammatory factors and slow the process of cell necrosis by inhibiting the phosphorylation of RIP3 and MLKL, thereby alleviating AP.

     

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