非甾体消炎药对大鼠小肠黏膜机械屏障功能的影响

Effect of non-steroidal anti-inflammatory drugs on small intestinal barrier function in rats

目的探讨非甾体消炎药对大鼠小肠黏膜机械屏障功能的影响。方法雄性sD大鼠32只，分为模型组和对照组，模型组予双氯芬酸灌胃，2次／d，每次7．5mg／kg，对照组使用相同剂量的生理盐水灌胃，分别按造模后1d和5d时相点分为2个亚组（每组8只）。进行胃及小肠大体损伤评分、小肠黏膜病理组织损伤评分，采用Carl Zeiss Imaging Systems图像分析系统进行绒毛高度、黏膜厚度、黏膜截面积定量分析，观察透射电镜下肠黏膜超微结构变化。结果模型组胃黏膜的损伤评分与对照组的差异无统计学意义。模型组第1天小肠黏膜可见散在红斑、糜烂和溃疡，溃疡沿肠系膜侧分布；第5天小肠黏膜可见出血、穿孔和窦道形成，其大体损伤评分均高于对照组（P〈0．05）。模型组第1天和第5天Chiu氏病理评分分别为3．5分和5．0分，与对照组相比差异有统计学意义（P〈0．05）。造模第1天大鼠空、回肠绒毛高度分别为（126．9±32．0）μm和（118．6±22．9）μm，较对照组显著降低（P〈0．05）；而空、回肠黏膜厚度、黏膜截面积和对照组相比差异无统计学意义，但有下降趋势；第5天大鼠空、回肠绒毛高度[（73．4±25．4）μm和（109．3±17．6）μm]显著降低、黏膜厚度[（123．8±51．6）μm和（165．7±37．4）μm]变薄、黏膜截面积[（2．48±1．01）mm。和（3．27±0．76）mm2]变小，与对照组相比差异均有统计学意义（P〈0．05）。透射电镜下见模型组第1天大鼠小肠黏膜微绒毛水肿、排列紊乱，线粒体肿胀，部分峪减少，内质网出现不同程度扩张，细胞间连接开始出现部分增宽；第5天小肠黏膜上皮微绒毛脱落更为明显，细胞连接断裂破坏严重。结论双氯芬酸可导致大鼠小肠黏膜屏障功能受损。绒毛变短、黏膜厚度变薄、微绒毛脱落和细胞间紧密连接增宽可能是其形态学基础。

Objective To approach the effect on mechanical barricade of the mucous membrane of small intestine caused by non-steroidal anti-inflammatory drugs （NSAIDs）. Methods Thirty-two male SD rats were randomly divided into control group and model group. The rats of the model group were given 7.5 mg/kg dielofenac by garage, bid ; the rats of the control group were given the same dose of saline. Then they were further randomly divided into two subgroups（ n = 8）at the first day and the fifth day after making the models to observe the scores of anatomical lesion on stomach and small intestine and the scores of tissue damage of mucous membrane and to quantitatively analyze the height of villi, as well as the thickness and the section area of mucous membrane with Carl Zeiss Imaging Systems. Observation of the change of ultrastructural organization of mucous membrane was carried out with transmission electron microscope. Results The mucous membrane of stomach of the model groups was slightly edematous. There was no difference between the scores of the model groups and control groups. It was seen that the mucous membrane of small intestine of the first day model group presented with erythema, anabrosis and ulcer. The ulcer was distributed along mesentery. The mucous membrane of small intestine of the fifth day model group showed bleeding, perforation and sinus tract formation, and the scores of anatomical lesion was higher than that of the control group （P 〈 0. 05 ）. The scroes of the lesions of the first and fifth day model groups were 3.5 and 5.0. The difference had statistical significance when compared with those of the control groups （ the scores were 0 ） （P 〈 0. 05 ）. Cell degeneration and cellular necrosis of epithelial mucosa of small intestine was also seen in the first day model group. The top of villi was ablated. The height of the pile on jejunum was （ 126. 9 ± 32. 0）μm and that on ileum was （ 118.6 ± 22. 9 ） μm. They were lower than those of the control group （P 〈 0. 05 ）. However there was no difference of the thickness and section area between them, but the thickness and section area showed a tendency of decrease. It was also seen that there were apomorphosis and sphacelism of epithelial ceils in the fifth day model group. Some villi were ablated and laminae propria exposed. The height of villi on jejunum [ （73.4 ± 25.4） μm] and that on ileum [ （ 109. 3 ± 17.6）μm] decreased significantly. The thickness of mucous membrane [ （ 123.8 ± 51.6） μm and （ 165.7 ± 37.4） μm ] decreased and the section area[ （2.48 ± 1.01 ） mm2 and （3.27 ± 0. 76） mm2 ] became smaller（P 〈 0. 05 vs control group）. The mucous membrane of the villi on small intestine was continuous but arranged disorderly. Cytocbondriome swelled, endocytoplasmic reticulia expanded with different degrees, intercellular junction widened partly. The microvilli in the fifth day model group were ablated more obviously and intercellular junctions were broken and destroyed gravely. Conclusions Diclofenac can cause damage to the function of mucous membrane barricade of small intestine. It could also lead to shortening of the villi, thinning of the mucous membrane, ablation of the microvilli, and widening of the tight intercellular junction as the characteristic morphological change.