舍曲林对肠易激综合征大鼠cAMP/PKA通路及肠道炎症反应的影响  

Effects of sertraline on cAMP/PKA pathway and intestinal inflammatory response in rats with irritable bowel syndrome

作　　者：范红云[1] 段志英[1] 赵亚男 杨春春[1] 杨明月 张梅 霍晓辉[1] 白云[2] 王竞[1] FAN Hongyun;DUAN Zhiying;ZHAO Yanan;YANG Chunchun;YANG Mingyue;ZHANG Mei;HUO Xiaohui;BAI Yun;WANG Jing(Department of Gastroenterology,the First Hospital of Hebei Medical University,Shijiazhuang 050031,China)

机构地区：[1]河北医科大学第一医院消化内科,石家庄050031 [2]河北省人民医院消化内科,石家庄050051

出　　处：《中国免疫学杂志》2022年第5期525-530,共6页Chinese Journal of Immunology

基　　金：河北省医学科学研究重点课题计划(20180227)。

摘　　要：目的:探讨舍曲林对肠易激综合征(IBS)大鼠环磷酸腺苷(cAMP)/环磷酸腺苷依赖性蛋白激酶A(PKA)通路及肠道炎症反应的影响。方法:采用母婴分离加醋酸灌肠联合结直肠扩张刺激法制备IBS大鼠模型,并将造模成功大鼠随机分为模型组、舍曲林低(10 mg/kg)、中(20 mg/kg)、高(30 mg/kg)剂量组和阳性对照组(匹维溴铵,2 mg/kg),每组15只,另取15只正常大鼠作为对照组,大鼠发育至9周龄时开始灌胃给药,对照组和模型组给予等体积生理盐水,其他各组给予相应药物,2次/d,连续10 d,10 ml/kg。末次给药结束后,观察记录各组大鼠一般情况、粪便含水量和排便时间;腹部撤回反射(AWF)评分法检测大鼠内脏敏感性;HE染色观察各组大鼠结肠组织病理学变化;ELISA检测各组大鼠结肠组织中TNF-α、IL-1β、IL-6和cAMP含量;Western blot检测各组大鼠结肠组织cAMP和PKA蛋白表达及cAMP反应元件结合蛋白(CREB)磷酸化水平。结果:对照组大鼠精神状态良好,发育正常,皮毛光亮,结肠组织肠黏膜屏障结构完整,无炎症因子浸润。与对照组相比,模型组大鼠状态较差,情绪烦躁易怒,活动较少,结肠组织出现明显水肿,肠黏膜完整性受损,出现大量炎症细胞浸润,排便时间、cAMP含量、cAMP、PKA蛋白表达及CREB磷酸化水平显著降低(P<0.05),粪便含水量、内脏敏感性、TNF-α、IL-1β和IL-6含量显著升高(P<0.05);与模型组相比,舍曲林低、中、高剂量组大鼠不良症状逐渐缓解,排便时间、cAMP含量、cAMP、PKA蛋白表达及CREB磷酸化水平依次升高(P<0.05),粪便含水量、内脏敏感性、TNF-α、IL-1β和IL-6含量依次降低(P<0.05);舍曲林高剂量组与阳性对照组各项指标差异无统计学意义(P>0.05)。结论:舍曲林可剂量依赖性改善IBS大鼠肠道炎症反应,可能与上调cAMP/PKA通路有关。Objective:To investigate effects of sertraline on cyclic adenosine monophosphate(cAMP)/cAMP-dependent protein kinase A(PKA)pathway and intestinal inflammatory response in rats with irritable bowel syndrome(IBS).Methods:IBS rat model was established by mother-infant separation,acetic acid enema and colorectal distention stimulation,rats successfully modeled were randomly divided into model group,sertraline low(10 mg/kg),medium(20 mg/kg),high(30 mg/kg)dose groups and positive control group(pinaverium bromide,2 mg/kg),with 15 rats in each group,another 15 normal rats were selected as control group.Rats were began to be given gastric administration at age of 9 weeks,control group and model group were given same volume of normal saline,and the other groups were given corresponding drugs,twice a day for 10 consecutive days,10 ml/kg.After the last drug administration,general condition,fecal water content and defecation time of rats in each group were observed and recorded;abdominal withdrawal reflex(AWF)score was used to detect visceral sensitivity;HE staining to observe histopathological changes of colon;contents of TNF-α,IL-1β,IL-6 and cAMP were detected by ELISA;Western blot to detect protein expressions of cAMP and PKA,and phosphorylation level of cAMP response element binding protein(CREB).Results:Rats in control group had good mental state,normal development,bright fur,intact intestinal mucosal barrier structure and no inflammatory factor infiltration.Compared with control group,rats in model group were in poor state,irritable,with less activity,obvious edema of colon tissue,damage of intestinal mucosal integrity,and a large number of inflammatory cell infiltration,defecation time,cAMP content,cAMP,PKA protein expressions and CREB phosphorylation level were significantly decreased(P<0.05),fecal water content,visceral sensitivity,TNF-α,IL-1βand IL-6 contents were significantly increased(P<0.05);compared with model group,adverse symptoms were gradually relieved in low,medium and high dose sertraline groups,defec

关 键 词：舍曲林 肠易激综合征 环磷酸腺苷/环磷酸腺苷依赖性蛋白激酶A 肠道炎症反应 

分 类 号：R574.4[医药卫生—消化系统]