Pan Zhi-yuan, Long Chao-liang, Wang Hai
Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2010 Apr;22(4):197-200.
To investigate the functional and morphological structure changes in the gut barrier of rats induced by cholinesterase inhibitor VX poisoning, and the therapeutic effect of benthiactzine.
Forty male Wistar rats were randomly divided into five groups: normal saline control group, VX poisoning (model) group, benthiactzine 1, 3, 9 mg/kg treatment groups, with 8 rats in each group. In the benthiactzine treatment groups, different dosages of the drug were respectively given (intraperitoneal injection) 5 minutes after VX poisoning (13 microg/kg subcutaneous injection). The plasma concentration of D-lactate and the diamine oxidase (DAO) activity, which reflected the gut barrier function, were measured at 3 hours after VX poisoning. At the same time point, the specimens from jejunum and ileum were harvested. The morphological changes in the intestinal mucosa were determined with light microscope and electron microscope.
After VX poisoning, the plasma D-lactate concentration and the DAO activity in model group were significantly increased compared with those of control group [D-lactate concentration in model group was (87.752 + or - 22.906) mg/L which was higher than that of control group (29.072 + or - 6.546) mg/L; DAO activity in model group was (6.72 + or - 0.93) U/L which was higher than that of control group (2.99 + or - 0.43) U/L, both P<0.01]. These values could be decreased dose-dependently after benthiactzine 1, 3, 9 mg/kg administration after the VX poisoning. Furthermore, the increase in D-lactate (45.290 + or - 11.141) mg/L and DAO activity (3.17 + or - 0.68) U/L could be totally reversed by 9 mg/kg of benthiactzine (both P<0.01). In model group, the intestinal mucosal epithelial injury was obvious at 3 hours after VX poisoning as shown under light microscope, including diminution of the mucosal thickness and the height of villi in jejunum and ileum, interstitial edema, angiotelectasis. Also electronic microscopic examination revealed damaged organelles and cell tight junction of mucosal epithelium. These pathological changes in intestine could be inhibited by benthiactzine in dose-dependent manner.
The gut barrier function in rats was seriously damaged by the cholinesterase inhibitor agents poisoning, as a result of injury to intestinal mucosa and increase of intestinal permeability. Benthiactzine exerts protection against functional and morphological structure damages of the gut barrier during intoxication.
探讨胆碱酯酶抑制剂VX中毒诱导大鼠肠道屏障的功能和形态结构变化，以及苯噻嗪的治疗作用。
40只雄性Wistar大鼠随机分为5组：生理盐水对照组、VX中毒（模型）组、苯噻嗪1、3、9mg/kg治疗组，每组8只。在苯噻嗪治疗组中，VX中毒（皮下注射13μg/kg）5分钟后分别给予不同剂量的药物（腹腔注射）。在VX中毒后3小时测量反映肠道屏障功能的血浆D-乳酸浓度和二胺氧化酶（DAO）活性。在同一时间点，采集空肠和回肠标本。用光镜和电镜观察肠黏膜的形态学变化。
VX中毒后，模型组血浆D-乳酸浓度和DAO活性均显著高于对照组[模型组D-乳酸浓度为（87.752±22.906）mg/L，高于对照组（29.072±6.546）mg/L；模型组DAO活性为（6.72±0.93）U/L，高于对照组（2.99±0.43）U/L，均P<0.01]。VX中毒后给予1、3、9mg/kg苯噻嗪后，这些值可呈剂量依赖性降低。此外，9mg/kg苯噻嗪可完全逆转D-乳酸（45.290±11.141）mg/L和DAO活性（3.17±0.68）U/L的升高（均P<0.01）。模型组在VX中毒后3小时光镜下可见肠黏膜上皮损伤明显，包括空肠和回肠黏膜厚度和绒毛高度减小、间质水肿、血管扩张。电镜检查还显示黏膜上皮细胞器受损和细胞紧密连接破坏。苯噻嗪可剂量依赖性抑制肠道的这些病理变化。
胆碱酯酶抑制剂中毒严重损害大鼠肠道屏障功能，其机制为肠黏膜损伤和肠道通透性增加。苯噻嗪在中毒期间对肠道屏障的功能和形态结构损伤具有保护作用。
