修回日期: 2004-06-09
接受日期: 2004-06-17
在线出版日期: 2004-09-15
目的: 研究胆汁反流在大鼠急性脑外伤后应激性溃疡中的作用, 探讨铝碳酸镁(达喜)对应激性溃疡的预防作用.
方法: 采用改良的Allen法建立大鼠颅脑外伤并发应激性溃疡模型, 将质量220-280 g ♂Wistar大鼠128只随机分为4组, 各组32只, 即: Ⅰ组应激组, Ⅱ组假手术组, Ⅲ组达喜预防组及Ⅳ组生理盐水对照组, 每组按颅脑外伤后1, 3, 6, 24 h时间点再分为4小组(每组8只). Ⅲ、Ⅳ两组动物手术前每日给予达喜500 mg/kg或生理盐水 1.5 mL 灌服3 d. 测定各组大鼠胃液及血清中总胆汁酸含量、胃液pH值、胃黏膜溃疡指数, 并观察胃黏膜大体及光镜下组织病理学改变.
结果: Ⅰ组各时点胃液总胆汁酸浓度明显高于Ⅱ组(P <0.05, P <0.01), 胃黏膜损伤严重(P <0.05), 二者呈线性相关(r = 0.55, P <0.01), 而血清总胆汁酸浓度及胃液pH值两组之间无明显差异, 组织学有相应改变. Ⅲ组各时点胃液总胆汁酸浓度明显低于Ⅳ组(P <0.01), 胃液pH值1, 3, 6 h 高于Ⅳ组(P <0.01), 溃疡指数6, 24 h小于Ⅳ组(P <0.01), 胃液总胆汁酸浓度及pH值与溃疡指数均呈线性相关(r = 0.43, r = 0.52, P <0.01); 组织学也观察到黏膜损伤明显减轻.
结论: 胆汁反流参与颅脑外伤应激性溃疡的发病; 胆汁反流程度与胃黏膜损伤程度正相关; 新型结合胆酸药物达喜预防应激性溃疡有良好作用.
引文著录: 王娟, 杨昭徐, 崔培林. 铝碳酸镁预防大鼠急性脑外伤后应激性溃疡的作用. 世界华人消化杂志 2004; 12(9): 2115-2118
Revised: June 9, 2004
Accepted: June 17, 2004
Published online: September 15, 2004
AIM: To study the role of bile reflux in the stress ulcer in rats after acute brain trauma, and to investigate the preventive role of Hydrotalcite (Talcid) to the stress ulcer.
METHODS: An animal model was established by Allen's method with modification. 128 male Wistar rats were divided randomly into four groups: Group I (n = 32): stress ulcer group, rats suffered from acute brain trauma without therapy; Group II (n = 32): normal control group, rats with sham operation; Group III (n = 32): Talcid group, rats suffered from acute brain trauma with Talcid administration; Group IV (n = 32): normal saline (NS) group, rats suffered from acute brain trauma with NS administration. Each group was divided into four subgroups of 1 h, 3 h, 6 h, and 24 h after the trauma (n = 8, for each subgroup). The rats in groups III and IV received Talcid and NS by gavage respectively before the operation for three days (Talcid: 500mg/kg.weight/day, NS: 1.5 mL/kg. weight/day). The bile acid concentration in the stomach and blood, the PH value and ulcer index (UI) were assayed, and the histology of gastric mucosa was analysed.
RESULTS: The concentration of gastric bile acid in group I was higher than that of group II at each time point (P <0.05, P <0.01); The damage of gastric mucosa was serious (P <0.05); and it showed a positive correlation between them (r = 0.05, P <0.01). But there was no difference in the blood bile acid and PH value. The histology showed corresponding changes. The concentration of gastric bile acid in group III was lower than that of group Ⅳ at each time point (P <0.01); The PH value at 1 h, 3 h, 6 h was higher but UI was lower at 6 h, 24 h in group III (P <0.01). There was a linear relationship between the gastric bile acid concentration or PH value and UI (r = 0.43, r = 0.52, P <0.01). The damage was ameliorated obviously in group III.
CONCLUSION: The bile reflux plays an important role in the stress ulcer after acute brain trauma. It shows a potential correlation between the extent of bile reflux and gastric mucosa damage. As a new combined bile acid drug, hydrotalcite can effectively prevent the occurrence of stress ulcer after acute brain trauma.
- Citation: Wang J, Yang ZX, Cui PL. Preventive effect of hydrotalcite on stress ulcer in rats after acute brain trauma. Shijie Huaren Xiaohua Zazhi 2004; 12(9): 2115-2118
- URL: https://www.wjgnet.com/1009-3079/full/v12/i9/2115.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v12.i9.2115
应激性溃疡(stress ulcer)是临床常见急症, 是机体在应激状态下所引起的急性胃黏膜糜烂、溃疡和出血, 在重症监护病房中发病率85-100%. 应激性溃疡的发病机制非常复杂, 目前尚未完全明了. 胆汁反流在应激性溃疡发病中的作用已有报道, 但有关胆汁反流在颅脑损伤引起的应激性溃疡的研究报道甚少. 我们建立大鼠颅脑外伤应激性溃疡模型, 检测血及胃液中总胆汁酸浓度、胃液pH值变化及他们与溃疡指数的关系, 探讨胆汁反流在应激性溃疡发病中的作用, 并观察有结合和清除胃内胆汁酸的药物达喜对应激性溃疡的防治作用.
质量220-280 g ♂ Wistar大鼠128只随机分为4组, 各组32只, 即: Ⅰ组应激组, Ⅱ组假手术组, Ⅲ组达喜预防组及Ⅳ组生理盐水对照组, 每组按颅脑外伤后1, 3, 6, 24 h时间点再分为4小组(每组8只). Ⅲ、Ⅳ两组动物手术前每日给予达喜500 mg/kg或生理盐水1.5 mL 灌服3 d. 实验仪器包括日立7170型全自动生化分析仪; 307-2B牙科台式电钻车(宁波医疗器械厂); 大鼠立体定位仪(国营西北光学仪器厂); 离心机(北京医用离心机厂); 精密pH试纸由北京化学厂提供. 药品包括德国拜耳公司生产的达喜(铝碳酸镁片), 100 mL/L水合氯醛胶浆10 mL由北京天坛医院制; 循环酶法总胆汁酸测定试剂盒为澳斯邦生物工程有限公司出品.
用改良的Allen法[1]建立颅脑外伤模型, 将禁食(自由饮水)24 h大鼠用100 mL/L水合氯醛ip麻醉 (4 mL/kg), 头部固定于立体定位仪上, 中线处切开头皮约4-5 cm, 剥离骨膜, 用牙科电钻于大鼠头颅齿状缝左旁2 mm, 冠状缝后1 mm, 人字缝前1 mm处钻孔至硬脑膜, 将中心粘有直径3 mm高4 mm圆柱体的硬塑料板(直径1 cm, 厚5 mm)放置于大鼠头部顶叶, 其中心圆柱体置于钻孔内, 于距硬塑料板上方50 cm高度将20 g砝码自由落下造成颅脑损伤模型后缝合头皮. Ⅰ组大鼠分别于颅脑损伤后禁食水1, 3, 6, 24 h后测定各项指标; Ⅱ组大鼠于切开头皮钻孔后不打击缝合头皮, 禁食水1, 3, 6, 24 h后测定各项指标; Ⅲ组大鼠每日灌服铝碳酸镁500 mg/kg×3 d, 最后1次给药后予颅脑损伤, 禁食水1, 3, 6, 24 h后测定各项指标; Ⅳ组大鼠每日灌服生理盐水1.5 mL×3 d, 最后1次给药后予颅脑损伤, 禁食水1, 3, 6, 24 h后测定各项指标. 大鼠用100 mL/L水合氯醛(4 mL/kg)麻醉后, 于剑突下正中切开腹壁, 游离胃, 口肛两端结扎, 向胃内注射蒸馏水1 mL, 反复翻转胃壁浸渍, 用管将胃液吸出, 用精密pH试纸测胃液pH值并加0.1 mol/L NaOH纠正至pH6.7-7.5, 心脏取血1 mL后处死大鼠, 将血与胃液以3 000 r/min离心15 min, 取上清液-20 ℃保存; 沿胃大弯侧剪开胃壁, 用生理盐水冲洗后评定溃疡指数(UI); 剪去一小块胃黏膜, 浸于40 g/L甲醛固定, 光镜下观察黏膜组织的病理变化. 观测胃液及血清的总胆汁酸含量, 用循环酶法测定; 胃液的pH值, 用精密pH试纸测定; 胃黏膜溃疡指数, 参照Guth标准评定, 即以胃黏膜斑点糜烂记1分, 糜烂长径<1 mm 记2分, 1-2 mm记3分, >2-3 mm记4分, ≥3 mm记5分, 按上述方法计分全胃得分之和即为溃疡指数; 光镜下观察黏膜组织的病理变化.
统计学处理 计量数据用均数±标准差表示, 采用Spss软件包, 对同一组中不同时间的计量资料用单因素方差分析, 对不同组间计量资料两两比较使用t检验, 用直线相关与回归分析溃疡指数与胃液、血胆汁酸浓度之间关系.
Ⅰ组大鼠于打击后1, 3 h可见胃黏膜弥漫性充血水肿, 无糜烂、出血、溃疡; 6 h胃黏膜出现点状糜烂; 24 h胃黏膜充血糜烂, 并见溃疡形成. Ⅱ组大鼠各时段胃黏膜表面光滑, 有粉红色光泽. Ⅲ组大鼠各时段胃黏膜出现不同程度的充血, 24 h组见少量点状糜烂, 无溃疡. Ⅳ组大鼠各时段胃黏膜表现同Ⅰ组. Ⅰ组1, 3 h组胃黏膜表光镜下表层血管充血及出血, 黏膜腺体肿胀, 黏膜层内有少量中性粒细胞浸润, 二者镜下无显著性差异; 6 h组较前二者损伤重, 镜下见黏膜上皮局部坏死脱落并伴出血; 24 h组最为严重, 黏膜层广泛出血坏死, 其损伤深度约达上皮全层上4/5, 并有大量中性粒细胞浸润. Ⅱ组大鼠各时段胃黏膜上皮均完整, 未见明显炎细胞浸润. Ⅳ组与Ⅰ组各时段胃黏膜表现相同. Ⅲ组1, 3, 6 h组胃壁各层结构基本正常, 黏膜上皮完整, 仅见表层血管扩张充血, 其与相对应的Ⅳ组各时段比较, 损伤均明显减轻; 24 h组黏膜上皮表层有轻度缺损, 上皮层见血管扩张, 与Ⅳ组24 h组比较, 损伤亦明显减轻.
Ⅰ, Ⅱ组各时点胃液胆汁酸浓度比较, 均有显著性差异(P <0.05, P <0.01, 表1), Ⅰ组内胃液胆汁酸浓度随时间延长有增加趋势, 观察期限内24 h最高, 除1 h与3 h间无统计学意义, 余均有显著性差异(P <0.05, 表 1); Ⅱ组各时点胃胆汁酸浓度无统计学意义. 两组间、组内各时点血胆酸浓度均无明显差异(P >0.05). Ⅰ组动物1, 3h胃黏膜无溃疡出现; 6, 24 h UI则有明显增大, 与Ⅱ组比较, 差异显著(P <0.01, 表2), Ⅰ组内24 h UI明显大于6 h(P <0.05, 表2). 两组间、组内各时点pH值比较均无统计学意义(P >0.05, 表3). 用线性相关与回归分析, 应激组胃液胆汁酸含量与溃疡指数之间存在线性正相关(r = 0.55, P <0.01), 而血胆汁酸、pH值则与溃疡指数之间无相关性(分别为r = 0.03, r = 0.05, P >0.05). 观察期内III组胃胆汁酸浓度逐渐增加, 1, 3 h间无明显差异, 但与6, 24 h间差异明显(P <0.05, 表1). III组各时点胃胆汁酸浓度明显低于IV组(P <0.01, 表1). 两组间、组内各时点血胆酸浓度均无明显差异(P >0.05). III组6, 24 h溃疡指数明显小于IV组相应时点(P <0.01, 表2). III组1, 3, 6h pH值明显高于IV组相应各时点(P <0.01, 表3), 但24 h两组无明显差异(P >0.05, 表3), 其与同组其他各时点相比, 均有显著性差异 (P <0.01, 表3). 线性相关与回归显示, 达喜组胃液胆汁酸、pH值与溃疡指数存在线性相关(分别为r = 0.43, r = 0.52, P <0.01), 而血胆汁酸则与溃疡指数无相关性(r = 0.01, P >0.05).
应激性溃疡的发病机制非常复杂, 他是多种因素综合作用的结果[1-10], 胆汁反流在应激性溃疡中的作用国内外虽有报道, 但目前对大鼠急性脑损伤后应激性溃疡过程中胆汁反流的作用研究甚少, 而对其预防则未见报道. 我们应用改良的Allen法[11]成功地建立起大鼠应激性溃疡模型, 组织形态学证实, 应激组大鼠胃黏膜有充血、水肿、糜烂、溃疡、出血, 而假手术组则无上述变化; 光镜下发现应激组胃黏膜表层血管充血及出血, 腺体肿胀, 黏膜上皮坏死脱落, 有中性粒细胞浸润, 假手术组胃黏膜上皮均完整, 未见明显炎细胞浸润. 通过观察大鼠颅脑损伤后胃黏膜损害发生发展的过程, 胃液胆汁酸、pH值以及血中胆汁酸含量的变化, 研究他们之间的关系, 探讨胆汁反流在颅脑损伤引起的应激性溃疡中的作用.
胆汁酸和胆盐对胃黏膜的致病作用早已为人们所关注[12-21], 十二指肠液中的胆汁一般不进入胃内, 应激时交感神经兴奋, 胃肠运动减弱, 幽门功能紊乱, 幽门常持续开放, 肠管胀气, 腹内压增高, 含胆汁的十二指肠液反流, 故可通过检测胃液胆汁酸含量了解胆汁反流的变化. 有学者研究了胆汁反流对残胃黏膜的作用, 发现胃黏膜组织学损伤的程度与胆汁酸浓度密切相关[22]; Cebra et al[23]对骆驼和羊驼的胃液进行分析, 发现有胃黏膜糜烂或溃疡的个体胃液胆汁酸浓度明显升高, 提出胆汁反流是引起胃黏膜损伤的原因之一; Cingi et al[24]通过结扎大鼠胆管建立大鼠梗阻性黄疸模型, 观察胆汁对胃黏膜的影响, 发现胃黏膜损伤的易感性有赖于胆汁是否能正常排入十二指肠, 胆汁排泄通畅者胃黏膜的损伤明显小于梗阻者, 提示胆汁在胃黏膜损伤的机制中起一定作用; 还有学者发现胆汁酸可引起大鼠胃黏膜跨膜电位差明显降低, 酸丢失增加, 大量H+反弥散入胃黏膜内, 产生组织学损伤[25-26]. 本实验中, 应激组与假手术组比较, 胃液胆汁酸含量明显增高(P <0.05, P <0.01), 且随着应激时间的延长, 胃内胆汁酸的含量逐渐增加, 其中1, 3 h组之间无显著性差异(P >0.05), 两组与6, 24 h组之间则有显著性差异(P <0.05), 胃黏膜的损伤亦逐渐加重(P <0.05), 其6、24 h组与假手术组相应时段比较有显著性差异(P <0.01), 且胃胆汁酸含量与溃疡指数呈正相关(r = 0.55, P <0.01), 而应激组与假手术组血胆汁酸含量及胃内pH值的变化则不大, 他们与溃疡指数之间亦无相关性. 实验结果说明, 应激时胃液胆汁酸含量明显增加, 提示胆汁反流亦明显增加, 其主要成分胆汁酸在应激性溃疡的发生中起着一定的作用, 胃液胆汁酸含量与胃黏膜损伤程度密切相关; 而血胆酸含量则与应激时胃黏膜的损伤程度不相关. 既往认为胃酸与黏膜损伤程度呈线性关系, 许多实验证明在应激性溃疡的形成中胃酸起一定的作用[27-30]. 本实验中, 应激组与假手术组胃液pH值虽有波动, 但变化不大, 可能是因为应激状态下胃黏膜缺血, 黏膜屏障破坏, 通透性增高, 氢离子逆弥散增加, 尽管氢离子以较高的浓度分泌, 但由于氢离子不断通过受损的胃黏膜屏障而丢失, 故应激组与假手术组胃液pH值的差别不易测出.
铝碳酸镁(达喜)为含有氢氧化铝、氢氧化镁、碳酸盐和水的化合物, 他是一单独的化学实体, 并存在于自然界的矿物质中, 具有独特的网状结构, 其既可在酸性环境下结合胃内胆汁酸, 又可中和胃酸, 当结合的胆汁酸进入肠内碱性环境时, 又将胆汁酸释放, 从而不影响胆酸的肠肝循环, 不影响营养物质的吸收, 故是一种新型结合胆酸药物. 本研究中, 应激前预先给予铝碳酸镁(达喜), 其1, 3, 6 h组胃黏膜仅有不同程度的充血, 24 h组见少量点状糜烂, 无溃疡. 光镜下胃壁各层结构基本正常, 黏膜上皮完整, 仅见表层血管扩张充血, 其与相对应的盐水组各时段比较, 损伤均明显减轻; 24 h组黏膜上皮表层有轻度缺损, 上皮层见血管扩张, 损伤较盐水组24 h组亦明显减轻. 同时发现, 达喜组各时段胃液胆汁酸含量虽随时间的延长而逐渐增高, 但与盐水组相应各时段比较, 其含量显著下降(P <0.01), 其1, 3 h组之间无显著性差异, 而与6、24 h组之间有显著性差异(P <0.05). 胃液胆汁酸含量与溃疡指数亦呈正相关(r = 0.43, P <0.01), 而血胆汁酸含量虽有变化, 但无显著性差异, 与溃疡指数无相关性(r = 0.01, P >0.05); 与盐水组相应各时段比较, 其1, 3, 6 h组胃液pH值明显升高(P <0.01), 24 h组则无显著性差异, 与溃疡指数存在负相关(r = 0.52, P <0.01), 此与达喜可中和胃酸有关. 本实验提示, 铝碳酸镁(达喜)可明显降低胃内胆汁酸含量, 且有中和胃酸的作用, 从而预防和减轻了应激性溃疡的发生, 他作为一种新型结合胆酸药物, 对预防和治疗应激性溃疡, 提供了一个新的思路. 本实验中, 达喜的有效时间仅数小时, 在达喜组停药24 h时段胃液胆汁酸仍处于较低水平, 其原因不详, 是否此药尚有其他作用机制未发现; 同时也给我们提出, 如在颅脑损伤后继续灌药, 是否能更有效地预防治疗应激性溃疡, 给临床以更有益的依据, 此是我们今后需进一步开展的工作.
总之, 应激性溃疡的发病是多种因素综合作用的结果, 本实验结果表明, 胆汁反流参与颅脑外伤并发应激性溃疡的发病; 胆汁反流程度与胃黏膜损伤程度正相关; 铝碳酸镁(达喜)可作为一种新型结合胆酸药物, 能有效预防应激性溃疡的产生.
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