环氧合酶-2对乙酸诱导大鼠胃溃疡形成和愈合的影响

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

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 16 0～ 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Westernblot分别检测胃粘膜中环氧合酶 2 (COX 2 )和诱导型一氧化氮合酶的表达。用ELISA测定胃粘膜中前列腺素E2 (PGE2 )量反映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。

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 6mg. 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 E 2 (PGE 2) 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 PGE 2 production were markedly increased in gastric mucosa after ulcer induction, especially in the basal part. After the treatment of NS-398, the increased PGE 2 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 PGE 2 production in iNOS expression and activity in gastric mucosa.