General Incorporated Association, Kyoto Research Center for Gastrointestinal Diseases, Karasuma- Oike, 671, Kyoto 604-8106. Japan.
Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto 607-8414. Japan.
Curr Pharm Des. 2017;23(27):4048-4056. doi: 10.2174/1381612823666170220154815.
We introduced a rat model of ischemic enteritis and investigated the roles of enterobacteria, Nitric Oxide (NO), and Prostaglandins (PGs) in its pathogenesis.
Male rats were used after 18 h of fasting. Ischemic enteritis was induced by partial ligation of the superior mesenteric artery (SMA). Under ether anesthesia, SMA was isolated, and a stenosis was made by placing a needle (23 guage) on the vessel and ligating both the vessel and needle, and then a needle was removed from the ligature. Animals were then fed normally after surgery. Various drugs such as antibiotics, cyclooxygenase (COX) inhibitors, NO synthase (NOS) inhibitors and PGE2 were administered for 2 days after surgery.
Stenosis of the SMA caused mucosal ischemia and damaged the small intestine, particularly the ileum, within 3 days. The development of enteritis was accompanied by mucosal invasion of enterobacteria, with the bacterial count being significantly increased 8 h after surgery. The severity of enteritis was prevented by the prior administration of ampicillin, L-NAME, or aminoguanidine, but aggravated by that of indomethacin or rofecoxib. The deleterious effects of indomethacin were antagonized by the co-administration of PGE2; these effects were mimicked by AE1-329, an EP4 agonist, and abrogated by AE3-208, an EP4 antagonist. The expression of iNOS and COX-2 was up-regulated in the small intestine in a time-dependent manner after ischemia caused by stenosis of the SMA, with increases in the mucosal contents of NO and PGE2.
These results suggest that enterobacteria played a major pathogenic role in this model of ischemic enteritis, and that iNOS/NO was deleterious in the pathogenesis of these lesions, while COX-2/PGE2 prevented the development of ischemic enteritis by activating EP4 receptors.
我们建立了一个缺血性肠炎的大鼠模型，并研究了肠杆菌、一氧化氮（NO）和前列腺素（PGs）在其发病机制中的作用。
雄性大鼠禁食 18 小时后使用。通过部分结扎肠系膜上动脉（SMA）来诱导缺血性肠炎。在乙醚麻醉下，分离 SMA，用 23 号针头（针号）在血管上做一个狭窄，然后将血管和针头都结扎，然后从结扎处取出针头。手术后，动物可以正常进食。手术后 2 天，给予抗生素、环氧化酶（COX）抑制剂、一氧化氮合酶（NOS）抑制剂和 PGE2 等各种药物。
SMA 狭窄导致黏膜缺血，3 天内小肠，特别是回肠受损。肠炎的发展伴随着肠杆菌的黏膜侵袭，术后 8 小时细菌计数明显增加。氨苄西林、L-NAME 或氨基胍的预先给药可预防肠炎的严重程度，但吲哚美辛或罗非昔布的给药会加重肠炎的严重程度。PGE2 的共同给予拮抗了吲哚美辛的有害作用；EP4 激动剂 AE1-329 模拟了这些作用，而 EP4 拮抗剂 AE3-208 则消除了这些作用。SMA 狭窄引起的缺血后，小肠中 iNOS 和 COX-2 的表达呈时间依赖性上调，黏膜中 NO 和 PGE2 的含量增加。
这些结果表明，肠杆菌在这种缺血性肠炎模型中起主要致病作用，iNOS/NO 在这些病变的发病机制中是有害的，而 COX-2/PGE2 通过激活 EP4 受体防止缺血性肠炎的发展。
