环氧合酶-2对乙酸诱导大鼠胃溃疡形成和愈合的影响

目的 研究选择性环氧合酶－2抑制剂对化学诱导胃溃疡形成和愈合的影响,同时探讨其可能机制。方法 雄性SD大鼠,体重160－180g。分两组,即单纯乙酸诱导胃溃疡作为对照组和乙酸诱导胃溃疡加NS－398处理组,各时间点每组均8只。乙酸诱导胃溃疡后1、3和7d用RT－PCR和Western blot分别检测胃粘膜中环氧合酶－2（COX－2）和诱导型一氧化合酶的表达。用ELIA测定胃粘膜中前列腺素E2(PGE2)最反映COX活性。同时研究选择性COX－2抑制剂NS398对iNOS表达、活性及胃粘膜损伤的影响,以溃疡面积来评估胃粘膜损伤程度。结果 RT－PCR结果显示乙酸诱导大鼠胃溃疡后,COX－2mRNA表达明显升高;以溃疡基底部为明显。胃粘膜PGE2合成也明显增高。NS－398能抑制胃粘膜PGE2的合成,溃疡诱导后1d处理组溃疡面积小于对照组,且周围充血水肿较轻;3d时两组溃疡大小无差异;但7d时NS－398组溃疡面积大于对照。同时NS－398能降低胃粘膜iNOS的表达及活性。结论 抑制COX－2活性能减轻溃疡形成初期炎症反应,使组织免受进一步损伤,但延缓溃疡愈合。这一作用除和PGE2合成减少有关外,可能尚和抑制iNOS表达和活性有关。

Effects of cyclooxygenase-2 on formation and healing of acetic acid-induced gastric ulcer in rats

OBJECTIVE: To investigate the possible role of cyclooxygenase-2 (COX-2) inhibitor NS-398 in formation and healing of acetic acid-induced gastric ulcer in rats. METHODS: Fourty eight male Sprague-Dawley rats weighed 160-180 g were perfused with acetic acid into the stomach to induce gastric ulcer and then divided into two groups. NS-398, a specific COX-2 antagonist, was injected subcutaneously 3 hours before and 21 hours after the perfusion with acetic acid and then injected every 24 hours with the dose of 6 mg.kg-1 to 24 rats (treatment group). The other 24 rats were injected subcutaneously with normal saline as controls. In both groups 8 rats were killed 1, 3, and 7 days after the induction of gastric ulcer by acetic acid respectively. RT-PCR and Western blotting were used to determine the expression of COX-2 mRNA and inducible nitric oxide synthase (iNOS) mRNA in the gastric mucosa at different time points. Prostaglandin E2(PGE2) concentration in gastric mucosa was determined by ELISA as a parameter reflecting the COX activity. The severity of ulcer was assessed by ulcer area. RESULTS: COX-2 mRNA expression and PGE2 production were markedly increased in gastric mucosa after ulcer induction, especially in the basal part. After the treatment of NS-398, the increased PGE2 production was inhibited. The ulcer area in NS-398 group was significantly smaller than that in control group 1 day after ulcer induction with slighter congestion and edema around the ulcer. There was no significant difference in ulcer area between NS-398 treatment group and control group 3 days after ulcer induction. However, the ulcer area in NS-398 treatment group was significantly greater than that in control group 7 days after ulcer induction. Along with the severity changes of mucosal lesion, the iNOS expression and activity decreased markedly in the NS-398 group. CONCLUSION: NS-398 inhibits COX-2 activity, thus alleviating inflammatory reaction in acetic acid induced gastric ulcer and averting further damage of tissues. However, it retards the ulcer healing by inhibiting PGE2 production in iNOS expression and activity in gastric mucosa.