兰索拉唑对乙醇诱导大鼠胃黏膜损伤的保护作用及其机制

Protective effect of lansoprazole against ethanol-induced gastric mucosal damage and its mechanism in rats

目的 研究兰索拉唑 (LP)对乙醇诱导大鼠胃黏膜损伤的保护作用 ,探讨胃泌素受体和环氧化酶 2 (COX 2 )表达在此过程中的作用。方法 大鼠ig给予LP 0 5、5、5 0mg·kg-1·d-1,或ig联合给予LP 5 0mg·kg-1·d-1和胃泌素受体拮抗剂AG 0 4 1R 3、10、30mg·kg-1·d-1,对照组ig给予羧甲基纤维素 (CMC) 2 5mg·kg-1·d-1,连续 14d。末次给药后 8h各组大鼠ig给予无水乙醇 1ml,观察胃损伤指数 (LI)及光镜下的胃黏膜病理学改变。酶免疫方法测定胃黏膜前列腺素E2 (PGE2 )水平 ,WesternBlot和免疫组化检测胃黏膜COX 2表达。评价特异性COX 2抑制剂NS 398对LP诱导的PGE2 合成及胃黏膜保护作用的影响。结果 在 0 5、5、5 0mg·kg-1LP组 ,LI分别为 (2 5 3± 0 33) %、(1 84±0 2 9) %和 (0 83± 0 12 ) % ,小于对照组 (3 6 5± 0 19) % (P<0 0 5 ) ;胃黏膜PGE2 含量分别为 (42 7± 32 ) ,(483± 12 1)和 (6 14± 82 ) pg·g-1wwt ,高于对照组 (2 6 6± 81) pg·g-1wwt(P <0 0 5 )。LP剂量依赖性地增加大鼠胃黏膜COX 2表达。然而 ,同时给予AG 0 4 1R阻断了LP诱导的胃黏膜保护作用、COX 2表达和PGE2 合成。NS 398抑制LP诱导的PGE2 合成及胃黏膜保护作用。

AIM To study the protective effect of lansoprazole (LP) against ethanol-induced gastric mucosal damage in rats and to clarify the role of gastrin receptor and cyclooxygenase-2 (COX-2) expression in LP-induced mucosal protective action. METHODS Rats were orally given 0.5, 5, and 50 mg·kg -1 ·d -1 lansoprazole alone or both lansoprazole (50 mg·kg -1 ·d -1 ) and a gastrin receptor antagonist AG-041R (3, 10, and 30 mg·kg -1 ·d -1 ) for 14 d. The control group was given 0.5% carboxymethylcellulose (CMC). Eight hours after the final administration of drugs, all rats were administered with 1 ml of absolute ethanol through an orogastric tube. Gastric lesion index (LI) was measured and morphological changes of gastric mucosa were assessed under light microscopy. The level of prostaglandin (PG) E_2 in gastric mucosa was measured by enzyme immunoassay (EIA). The expression of COX-1 and COX-2 in the gastric mucosa was analyzed using Western blot and immunohistochemical staining. The effects of a specific COX-2 inhibitor NS-398 on PGE_2 in the gastric mucosa and the mucosal protection afforded by lansoprazole were evaluated. RESULTS LI induced by ethanol were (2.53±0.33)%, (1.84±0.29)% and (0.83±0.12)% in the groups treated with 0.5, 5, or 50 mg·kg -1 of LP respectively, which were significantly lower than that in the control group treated with CMC (3.65±0.19)% (P<0.05). The gastric mucosal PGE_2 levels were (427±32), (483±121) and [FQ(12。46,X-WZ]-(614±82) pg·g -1 wwt respectively in the LP groups and (266±81) pg·g -1 wwt in the control group (P<0.05). LP dose dependently increased the mucosal expression of COX-2 but not that of COX-1. However, concomitant administration of AG-041R abolished LP-induced mucosal protection, increased COX-2 expression and mucosal PGE_2. NS-398 blocked LP-induced mucosal PGE_2 synthesis and mucosal protection. CONCLUSION The gastric mucosal protection of LP is related to induce COX-2 expression and increase PGE_2 synthesis in gastric mucosa. Activation of gastrin receptor by endogenous gastrin plays an important role in the effects of LP on COX-2 up-regulation and mucosal protection in the rat stomach.-