药学学报, 2018, 53(10): 1652-1659
引用本文:
周雪沁, 苏畅, 李晓桐, 于雪敏, 齐淑婉, 刘涛, 张敬美, 姚静. N-对氯苯磺酰基-4-氨基水杨酸抑制DSS诱导的溃疡性结肠炎的作用[J]. 药学学报, 2018, 53(10): 1652-1659.
ZHOU Xue-qin, SU Chang, LI Xiao-tong, YU Xue-min, QI Shu-wan, LIU Tao, ZHANG Jing-mei, YAO Jing. The inhibitory effect of N-p-chlorobenzenesulfonyl-4-aminosalicylic acid on dextran sodium sulfate-induced ulcerative colitis[J]. Acta Pharmaceutica Sinica, 2018, 53(10): 1652-1659.

N-对氯苯磺酰基-4-氨基水杨酸抑制DSS诱导的溃疡性结肠炎的作用
周雪沁1, 苏畅1, 李晓桐1, 于雪敏1, 齐淑婉1, 刘涛2, 张敬美3, 姚静4
1. 济宁医学院临床医学院, 山东 济宁 272067;
2. 济宁医学院附属医院, 山东 济宁 272067;
3. 济宁医学院行为医学教育研究所, 山东 济宁 272067;
4. 济宁医学院基础医学院, 山东 济宁 272067
摘要:
本研究旨在探讨N-对氯苯磺酰基-4-氨基水杨酸对葡聚糖硫酸钠(dextran sodium sulfate,DSS)诱导的溃疡性结肠炎的治疗作用。将60只BALB/c小鼠随机分为空白组、DSS模型组、5-氨基水杨酸(5-amino salicylic acid,5-ASA)组、给药组,每组10只,空白组正常饮水,其他各组均饮用质量浓度(w/v)为0.04的DSS,5-ASA组(40 mg·kg-1)、N-对氯苯磺酰基-4-氨基水杨酸(10、20、40 mg·kg-1)采用灌胃给药方式。实验期间每日测量小鼠体重,观察各组小鼠大便形态(大便是否成形)和肉眼血便情况以及精神状态等。建模10天,取血后处死小鼠,解剖并摘取重要脏器以及结肠组织,称取脏器重量,测量结肠长度。通过苏木精-伊红(hematoxylin and eosin,HE)染色对各组小鼠的重要脏器(心、肝、肺、肾)和结肠组织进行病理学评分。通过ELISA检测血清中肿瘤坏死因子α(tumor necrosis factor alpha,TNF-α)、白细胞介素1β(interleukin 1 beta,IL-1β)、白细胞介素6(interleukin 6,IL-6)、巨噬细胞炎性蛋白2(macrophage inflammatory protein 2,MIP-2)、髓过氧化物酶(myeloperoxidase,MPO)等炎症因子的表达。实验结果显示,建模第4天,DSS模型组小鼠出现便血的情况,第7日模型组便血小鼠数量上升至10只,造模后5-ASA组及给药组小鼠出现便血和腹泻。DSS模型组小鼠从建模第4天起出现精神状态差,体重下降明显,给药组和5-ASA组小鼠精神状态较好,体重接近于空白组小鼠(P < 0.01)。给药组的结肠长度明显大于DSS模型组。HE染色结果显示,DSS模型组小鼠结肠黏膜层出现重度炎症细胞浸润,局部出现不同程度的坏死,坏死处已有成纤维细胞增生,黏膜肌层组织出现炎症细胞浸润;中剂量组(20 mg·kg-1)结肠黏膜表现为轻度慢性炎症和少量炎性细胞浸润,情况略有改善;高剂量组(40 mg·kg-1)小鼠结肠黏膜结构基本恢复正常,上皮结构较完整,少量炎症细胞浸润。ELISA结果显示,给药组小鼠血清中IL-1β、IL-6、TNF-α、MIP-2及MPO的含量较模型组显著降低。因此可以得出,N-对氯苯磺酰基-4-氨基水杨酸有治疗DSS诱导UC模型的作用。
关键词:    N-对氯苯磺酰基-4-氨基水杨酸      葡聚糖硫酸钠      溃疡性结肠炎      炎症因子      巨噬细胞炎性蛋白2      髓过氧化物酶     
The inhibitory effect of N-p-chlorobenzenesulfonyl-4-aminosalicylic acid on dextran sodium sulfate-induced ulcerative colitis
ZHOU Xue-qin1, SU Chang1, LI Xiao-tong1, YU Xue-min1, QI Shu-wan1, LIU Tao2, ZHANG Jing-mei3, YAO Jing4
1. School of Clinical Medicine, Jining Medical University, Jining 272067, China;
2. Affiliated Hospital, Jining Medical University, Jining 272067, China;
3. Institute of Behavioral Medicine Education, Jining Medical University, Jining 272067, China;
4. School of Basic Medicine, Jining Medical University, Jining 272067, China
Abstract:
The study aims to explore the effects of N-p-chlorobenzenesulfonyl-4-amino salicylic acid on the dextran sodium sulfate (DSS)-induced ulcerative colitis in mouse. A total of 60 BALB/c mice were randomly divided into 6 groups (n=10):control group, DSS model group, 5-amino salicylic acid (5-ASA) group, and administration groups (N-p-chlorobenzenesulfonyl-4-aminosalicylic acid) 10, 20, 40 mg·kg-1. Model group were induced by drinking 4% (w/v) DSS solution for 7 days and normal water for the next 3 days. The positive group and drug group mouse were given 5-ASA (40 mg·kg-1) and N-p-chlorobenzene sulfonyl-4-amino salicylic acid (10, 20, 40 mg·kg-1) by gavage respectively. During the experiment, changes in body weight, bloody stool, fecal character and mental status were observed daily. Damage and repair of the colon mucosa and the pathological changes of important organs were observed by hematoxylin and eosin (HE) staining. Expression of inflammatory factors such as tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), macrophage inflammatory protein 2 (MIP-2), myeloperoxidase (MPO) in serum were detected by ELISA. The results showed that bloody stools and diarrhea emerged on the 4th day after model establishment in model mice. The number of bloody mice rose to ten, and blood and diarrhea began to appear in the administration group on the 7th day. Mental status was poor and body weight decreased significantly in model group since the 4th day, and the situation was improved in the administration group and 5-ASA group. Colons in the administration groups (10, 20, 40 mg·kg-1) were longer than those in the DSS model group. In the DSS model group, the colonic mucosa and submucosa of mice exhibited severe inflammatory cell infiltration, various degrees of necrosis, proliferation. In the middle dose group (20 mg·kg-1), the situation has improved slightly and the colonic mucosa showed mildly chronic inflammation and a small amount of inflammatory cells infiltration. The high dose group (40 mg·kg-1) showed normal colon mucosal, relatively complete epithelial structure and few inflammatory cell infiltration. The levels of IL-1β, IL-6, TNF-α, MIP-2 and MPO in the serum of mice were lower in the administration group (40 mg·kg-1) than in model group. Therefore, N-p-chlorobenzenesulfonyl-4-amino salicylic acid might be a feasible treatment for DSS-induced UC.
Key words:    N-p-chlorobenzenesulfonyl-4-amino salicylic acid    dextran sodium sulfate    ulcerative colitis    inflammatory factor    macrophage inflammatory protein 2    myeloperoxidase    
收稿日期: 2018-06-18
DOI: 10.16438/j.0513-4870.2018-0567
基金项目: 国家自然科学基金青年基金资助项目(81603143);济宁医学院博士基金资助项目(JY2015BS08);山东省高等学校国家级大学生创新创业训练计划项目(201710443013).
通讯作者: 姚静,Tel:86-537-3616286,E-mail:yjing_87@163.com
Email: yjing_87@163.com
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