四神丸改善肠道屏障功能缓解伊立替康肠道毒性的研究  

Sishen pill alleviating irinotecan-triggered intestinal toxicity via improving intestinal barrier function

作　　者：朱姣姣 朱晓俊 严自强 ZHU Jiao-jiao;ZHU Xiao-jun;YAN Zi-qiang(Department of Emergency,Changhai Hospital,Naval Medical University,Shanghai 200433;Department of Pharmacy,Changhai Hospital,Naval Medical University,Shanghai 200433)

机构地区：[1]海军军医大学附属长海医院急诊科,上海200433 [2]海军军医大学附属长海医院药剂科,上海200433

出　　处：《中南药学》2025年第1期94-99,共6页Central South Pharmacy

基　　金：上海市普陀区卫生系统科技创新项目(No.ptkwws202204)。

摘　　要：目的研究四神丸对伊立替康肠道毒性的改善作用及其作用机制。方法将小鼠分为对照组,模型组(伊立替康75 mg·kg^(-1))和四神丸低、高剂量(2.5、5 g·kg^(-1))组及阳性药组(洛哌丁胺10 mg·kg^(-1))。记录小鼠体重变化,DAI评分,粪便隐血情况,结肠组织病理学变化,炎症因子肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)的表达,观察四神丸对伊立替康肠道毒性的改善作用;采用灌胃FITC标记葡聚糖,4 h后检测血清中的荧光强度、脂多糖(LPS)和二胺氧化酶(DAO)含量,观察四神丸对伊立替康小鼠肠道通透性的影响;采用Western blot和免疫荧光检测小鼠结肠组织中紧密连接蛋白(ZO-1、Occludin和Claudin)的表达,观察四神丸对伊立替康小鼠肠道屏障的影响。结果与对照组比较,模型组小鼠体重明显降低,DAI评分、小鼠粪便隐血阳性率、结肠组织中炎症因子(TNF-α、IL-1β和IL-6)的表达显著升高(P<0.01);小鼠血清中荧光强度、LPS和DAO含量明显增多;小鼠结肠组织中ZO-1、Occludin和Claudin的表达显著降低(P<0.01)。四神丸低、高剂量干预后,小鼠体重显著恢复,DAI评分、小鼠粪便隐血阳性率和小鼠结肠组织中TNF-α、IL-1β、IL-6、ZO-1、Occludin和Claudin的表达明显降低(P<0.05,P<0.01);小鼠肠道通透性显著改善(P<0.01)。结论四神丸可以有效改善伊立替康的肠道毒性,其作用机制可能与促进紧密连接蛋白(ZO-1、Occludin和Claudin)的表达从而恢复肠道屏障功能有关。Objective To determine the ameliorating effect of Sishen pill on irinotecan-triggered intestinal toxicity and related mechanism.Methods The mice were divided into a control group,a model group(irinotecan 75 mg·kg^(-1)),Sishen pill low dose and high dose(2.5 and 5 g·kg^(-1))groups and a positive group(loperamide 10 mg·kg^(-1)).The effects of Sishen pill on alleviating the irinotecan triggered intestinal toxicity were determined by recording the body weight,DAI scores,fecal occult blood,colonic and histopathology and the expressions of inflammatory factors[tumor necrosis factorα(TNF-α),interleukin 1β(IL-1β),and interleukin 6(IL-6)].The effects of Sishen pill on the intestinal permeability,lipopolysaccharide(LPS)and diamine oxidase(DAO)contents were observed by fluorescence intensity in the serum 4 h after intragastric administration of FITC-dextran.The effects of Sishen pill on the intestinal barrier of irinotican mice were observed by the expression of ZO-1,Occludin and Claudin in the colon tissue,detected by Western blot and immunofluorescence.Results The weight was markedly decreased(P<0.01),while the DAI score,fecal occult blood positive rate,and the expression of TNF-α,IL-1βand IL-6 greatly increased,the fluorescence intensity,LPS and DAO contents obviously increased,but the expressions of ZO-1,Occludin and Claudin were significantly decreased in the model group,compared with those of the control group(P<0.01).The body weight of the mice recovered significantly(P<0.01),the DAI scores,fecal occult blood positive rate,the expressions of TNF-α,IL-1β,IL-6,ZO-1,Occludin and Claudin were decreased significantly after the intervention of both low and high doses of Sishen pill(P<0.05 and P<0.01).The intestinal permeability of mice was significantly improved(P<0.01).Conclusion Sishen pill effectively alleviates irinotecan triggered intestinal toxicity,the mechanism may be related to promoting the expression of tight junction proteins(ZO-1,Occludin and Claudin)to restore the intestinal barrier function.

关 键 词：伊立替康 肠道毒性 四神丸 肠道屏障 紧密连接蛋白 

分 类 号：R286[医药卫生—中药学]