Anti-inflammatory and antisecretory potential of histidine in Salmonella-challenged mouse small intestine.
Anti-inflammatory and antisecretory potential of histidine in Salmonella-challenged mouse small intestine.
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发表时间：
1998-05
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通讯作者：
J. Peterson;I. Boldogh;V. Popov;S. Saini;A. Chopra
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作者：
J. Peterson;I. Boldogh;V. Popov;S. Saini;A. Chopra
用鼠伤寒沙门氏菌攻击小鼠小肠，可引起肠腔积液、急性炎症以及组织学和电子显微镜下对小肠粘膜的广泛结构破坏。腹腔和肠腔注射L组氨酸，一种已知的抗氧化剂，减少在肠腔内积累的液体量，并保护肠道组织免受鼠伤寒沙门氏菌的损害。L组氨酸对鼠伤寒沙门氏菌液体蓄积的抑制作用是L对映体所特有的，因为D-组氨酸对小鼠伤寒沙门氏菌无明显保护作用。L组氨酸对感染肠道组织的保护作用归因于咪唑环清除肠道细胞在急性炎症反应中产生的活性氧(ROS)的能力。由于ROS的产生，鼠伤寒沙门氏菌攻击的炎症肠道组织中的谷胱甘肽水平显著降低。重要的是，在给予鼠伤寒沙门氏菌攻击小鼠L组氨酸后，小肠组织中谷胱甘肽的含量与模拟攻击对照组没有显著差异。支持这一机制的进一步证据包括L-组氨酸清除单核细胞内毒素暴露产生的ROS的能力(U937)，氧化还原敏感的荧光染料(2‘7’-二氯二氢荧光素[DCF])证实了这一点。流式细胞仪检测显示，在脂多糖暴露前向U937细胞培养液中加入L组氨酸和少量的D组氨酸，可显著降低脂多糖诱导的细胞内DCF的荧光强度，且呈剂量依赖性。含有L组氨酸结构的抗炎药的潜在治疗价值可以保护感染的粘膜组织，而不受微生物病原学的影响。
Challenge of mouse small intestinal loops with Salmonella typhimurium invoked the accumulation of luminal fluid, acute inflammation, and extensive structural damage to the small intestinal mucosa, as determined by histology and electron microscopy. Intraperitoneal and intestinal luminal injection of L-histidine, a known antioxidant, reduced the amount of fluid accumulating in the intestinal lumen and protected the intestinal tissue from S. typhimurium-induced damage. The reduction in S. typhimurium-induced fluid accumulation by L-histidine was specific for the L-enantiomer because D-histidine had no significant protective effect. Efficacy of L-histidine in protecting the infected intestinal tissue was attributed to the capacity of the imidazole ring to scavenge reactive oxygen species (ROS) generated by cells in the intestine during the acute inflammatory response. Glutathione levels were markedly reduced in S. typhimurium-challenged, inflamed intestinal tissues as a result of ROS generation. Importantly, after dosing the S. typhimurium-challenged mice with L-histidine, the glutathione content of the small intestinal tissue was not significantly different from mock-challenged controls. Further evidence favoring this mechanism included the capacity of L-histidine to scavenge ROS produced as a result of lipopolysaccharide (LPS) exposure of mononuclear cells (U937), as demonstrated with a redox-sensitive fluorescent dye (2'7'-dichlorodihydrofluorescein [DCF]). Addition of L-histidine, and to a lesser extent D-histidine, to the culture media of U937 cells before LPS exposure, resulted in a significant dose-dependent reduction in LPS-induced intracellular DCF fluorescence, as measured quantitatively by flow cytometry. The potential therapeutic value of anti-inflammatory drugs containing an L-histidine-like structure could protect infected mucosal tissues irrespective of microbial etiology.