Kanatani K, Ebata M, Murakami M, Okabe S
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
J Physiol Pharmacol. 2004 Mar;55(1 Pt 2):207-22.
This study examined the effects of indomethacin and rofecoxib on normal and Helicobacter pylori (H. pylori)-infected gastric mucosa of Mongolian (M.) gerbils. M. gerbils (6-wk-old) were orally administered H. pylori (ATCC43504, 2 x 10(8) CFU/ml) after fasting for 24 hours. Beginning 3 mo after inoculation, indomethacin (2 mg/kg, s.c) or rofecoxib (10 mg/kg, p.o.) was administered once daily for 2 wk to the gerbils. At autopsy, gastric mucosal ulcer area, myeroperoxidase (MPO) activity, prostaglandin (PG) E(2) synthesis, and H. pylori viability were determined. Histamine-stimulated gastric acid secretion was measured with the acute gastric fistula method. Histological study was performed with H&E staining. H. pylori infection caused severe mucosal damage and production of lymphoid follicles in the gastric submucosa. In H. pylori-infected gerbils, indomethacin aggravated the gastric mucosal damage induced by H. pylori infection. Furthermore, indomethacin by itself induced gastric ulcers at an incidence of 6/10. In contrast, rofecoxib did not aggravate the H. pylori-induced mucosal damage. Indomethacin and rofeocoxib significantly reduced H. pylori viability. MPO activity was significantly increased in H. pylori-infected gerbils compared with H. pylori-uninfected gerbils. Indomethacin and rofecoxib reduced MPO activity in H. pylori-infected gerbils. PGE(2) synthesis was markedly increased in H. pylori-infected gerbils (approximately 3-times) compared with the normal gerbils. Indomethacin significantly inhibited PGE(2) synthesis in the gastric mucosa, both in normal and H. pylori-infected gerbils. Rofecoxib did not reduce PGE(2) synthesis in normal gerbils, however, PGE(2) synthesis was reduced to normal levels in H. pylori-infected gerbils. In H. pylori-infected gerbils, histamine-stimulated gastric acid secretion was reduced compared with normal gerbils. Indomethacin significantly increased histamine-stimulated gastric acid secretion and rofecoxib tended to increase secretion in H. pylori-infected gerbils. It was concluded that indomethacin enhances development of gastric mucosal damage in normal gerbils and aggravates H. pylori-induced gastric damage, resulting in gastric ulcers. Rofecoxib did not induce gastric damage in normal gerbils and did not aggravate damage in H. pylori-infected gerbils, suggesting that rofecoxib is less damaging to the stomach than indomethacin.
本研究检测了吲哚美辛和罗非昔布对蒙古沙鼠正常及幽门螺杆菌（H. pylori）感染的胃黏膜的影响。6周龄蒙古沙鼠禁食24小时后经口给予幽门螺杆菌（ATCC43504，2×10⁸CFU/ml）。接种3个月后，对沙鼠每日一次给予吲哚美辛（2mg/kg，皮下注射）或罗非昔布（10mg/kg，口服），持续2周。尸检时，测定胃黏膜溃疡面积、髓过氧化物酶（MPO）活性、前列腺素（PG）E₂合成及幽门螺杆菌活力。采用急性胃瘘法测定组胺刺激的胃酸分泌。用苏木精-伊红（H&E）染色进行组织学研究。幽门螺杆菌感染导致胃黏膜严重损伤及胃黏膜下层淋巴滤泡形成。在幽门螺杆菌感染的沙鼠中，吲哚美辛加重了幽门螺杆菌感染所致的胃黏膜损伤。此外，吲哚美辛自身诱导胃溃疡的发生率为6/10。相比之下，罗非昔布未加重幽门螺杆菌诱导的黏膜损伤。吲哚美辛和罗非昔布显著降低幽门螺杆菌活力。与未感染幽门螺杆菌的沙鼠相比，感染幽门螺杆菌的沙鼠MPO活性显著升高。吲哚美辛和罗非昔布降低了感染幽门螺杆菌沙鼠的MPO活性。与正常沙鼠相比，感染幽门螺杆菌的沙鼠PGE₂合成显著增加（约3倍）。吲哚美辛显著抑制正常及感染幽门螺杆菌沙鼠胃黏膜中的PGE₂合成。罗非昔布未降低正常沙鼠的PGE₂合成，然而，在感染幽门螺杆菌的沙鼠中PGE₂合成降至正常水平。在感染幽门螺杆菌的沙鼠中，与正常沙鼠相比，组胺刺激的胃酸分泌减少。吲哚美辛显著增加感染幽门螺杆菌沙鼠中组胺刺激的胃酸分泌，罗非昔布倾向于增加其分泌。得出的结论是，吲哚美辛增强正常沙鼠胃黏膜损伤的发展并加重幽门螺杆菌诱导的胃损伤，导致胃溃疡。罗非昔布在正常沙鼠中未诱导胃损伤，在感染幽门螺杆菌的沙鼠中也未加重损伤，提示罗非昔布对胃的损伤小于吲哚美辛。
