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Studies on a graft-protective effect of nitric oxide in small bowel transplantation

一氧化氮在小肠移植中的移植物保护作用研究

基本信息

批准号：
17591870
负责人：
HAMADA Yoshinori
金额：
$ 1.92万
依托单位：
Kansai Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591870/
关键词：
rat small bowel transplantation epidermal growth factor intestinal adaptation bacterial translocation nitric oxide interleukin-1β inducible nitric oxide synthase pitavastatin intestinal adaptation intestinal endothelical cells nitric o

项目摘要

[Background/Aims] Epidermal growth factor (EGF), which is one of trophic factors for intestinal adaptation after small bowel transplantation (SBT), has been shown to prevent bacterial translocation (BT) in a variety of experimental animal models. Nitric oxide (NO) may be an important protective molecule against gut-derived sepsis, bum injury, intestinal ulcerogenecity, intestinal lesions, and SBT. Recently we found that EGF increased the production of NO in rat intestinal epithelial cells stimulated by pro-inflammatory cytokine, interleukin (IL)-1β, suggesting that NO may be involved in the cytoprotective effects of EGF against intestinal injury. We examined whether drugs, which have protective effects in various organ injuries, influence the inducible nitric oxide synthase (iNOS) expression and NO production in intestinal epithelium.[Methods] Cultured rat intestinal epithelial cells (IEC-6) were treated with IL-1β /EGF in the presence of drugs, and the induction of iNOS and NO product … More ion was analyzed.[Results] IEC-6 stimulated the production of NO in the presence of IL-1β /EGF. The addition of anti-oxidant such as a-lipoic acid and cysteamine, free radical scavenger edaravone (Mitsubishi Wellpharma, Japan), and HMG-CoA reductase inhibitor/statin pitavastatin (Kowa, Japan) further increased the NO production. Among them, pitavastatin (10-100 μM) accelerated the NO production in the presence of IL-1β as in the case of EGF, showing a maximal effect at the concentration of 50 μM. Pitavastatin alone had no effect on the production of NO. Pitavastatin increased the levels of iNOS mRNA, followed by the increase of iNOS protein, which in turn enhanced the NO production. Exogenous addition of mevalonate, which is a key intermediate of cholesterol biosynthesis and is reduced by statins, blocked the increased production of NO, and increased expression of iNOS mRNA and protein. This suggests that the stimulatory effect of pitavastatin is at least in part through the inhibition of cholesterol biosynthesis.[Conclusion] Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors), which are originally used to lower plasma cholesterol levels, are increasingly recognized as anti-inflammatory agents. Our results indicate that pitavastatin up-regulate the induction of iNOS expression and increase the production of NO, resulting in the protective effect in intestinal epithelial cells during inflammation. Pitavastatin as well as EGF may accelerate the graft adaptation through the regulation of NO production in SBT. Less

[背景/目的] 表皮生长因子（EGF）是小肠移植（SBT）后肠道适应的营养因子之一，在多种实验动物模型中已被证明可以防止细菌易位（BT）。一氧化氮 (NO) 可能是对抗肠源性脓毒症、烧伤损伤、肠溃疡发生、肠道损伤和 SBT 的重要保护分子。最近我们发现EGF增加了促炎细胞因子白细胞介素(IL)-1β刺激的大鼠肠上皮细胞中NO的产生，表明NO可能参与了EGF对抗肠道损伤的细胞保护作用。我们检测了对各种器官损伤具有保护作用的药物是否影响肠上皮中诱导型一氧化氮合酶（iNOS）表达和NO生成。[方法]在药物存在下用IL-1β/EGF处理培养的大鼠肠上皮细胞（IEC-6），分析iNOS和NO产物离子的诱导。[结果]IEC-6刺激在 IL-1β /EGF 存在的情况下产生 NO。添加抗氧化剂如α-硫辛酸和半胱胺、自由基清除剂依达拉奉（Mitsubishi Wellpharma，日本）和HMG-CoA还原酶抑制剂/他汀类匹伐他汀（Kowa，日本）进一步增加了NO的产生。其中，匹伐他汀（10-100 μM）与 EGF 一样，在 IL-1β 存在的情况下加速 NO 的产生，在 50 μM 浓度时显示出最大效果。单独使用匹伐他汀对 NO 的产生没有影响。匹伐他汀增加 iNOS mRNA 的水平，随后增加 iNOS 蛋白，从而增加 NO 的产生。外源添加甲羟戊酸（胆固醇生物合成的关键中间体并被他汀类药物减少）可阻止 NO 产生的增加，并增加 iNOS mRNA 和蛋白质的表达。这表明匹伐他汀的刺激作用至少部分是通过抑制胆固醇生物合成而产生的。【结论】他汀类药物（3-羟基-3-甲基-戊二酰辅酶A（HMG-CoA）还原酶抑制剂）最初用于降低血浆胆固醇水平，现在越来越多地被认为是抗炎药。我们的结果表明，匹伐他汀上调 iNOS 表达的诱导并增加 NO 的产生，从而在炎症期间对肠上皮细胞产生保护作用。 Pitavastatin 和 EGF 可能通过调节 SBT 中 NO 的产生来加速移植物适应。较少的