Hirose M, Miwa H, Kobayashi O, Oshida K, Misawa H, Kurosawa A, Watanabe S, Sato N
Department of Gastroenterology, Juntendo University, School of Medicine, Tokyo, Japan.
Aliment Pharmacol Ther. 2002 Apr;16 Suppl 2:83-9. doi: 10.1046/j.1365-2036.16.s2.28.x.
Cyclooxygenase-2 (COX-2) is one of the rate-limiting enzymes for prostaglandin synthesis from arachidonic acid. Although it is known that inhibition of cyclooxygenase activity delays ulcer healing, the regulatory relationship between COX-2 and its metabolites in gastric epithelial cell proliferation is not well known.
To investigate whether COX-2 has an effect on gastric mucosal cell proliferation and further studied whether such effect is mediated only by prostaglandin E2 (PGE2), a representative metabolite of arachidonates in the gastric mucosa.
Artificial wounds of defined area size were created on complete monolayer cell sheets of isolated rat gastric epithelial cells and rat gastric cell line RGM1 under the addition of arachidonic acid or a COX-2 selective inhibitor, JTE522. Repair of wounds was assessed by monitoring wound size, with cell proliferation detected using 5-bromodeoxyuridine staining. Quantity of secreted PGE2 was measured by enzyme immunoassay.
Stimulation of foetal calf serum increased the expression of COX-2 protein and inhibition of COX-2 retarded wound healing with reduction of cell proliferation. Arachidonic acid increased PGE2 production and accelerated restoration. Combination of JTE522 and arachidonic acid resulted in a marked retardation of wound healing compared to the control, but JTE522 did not completely suppress the increase in cellular PGE2 content following the addition of arachidonate.
The difference in the effects of JTE522 on PGE2 production and on wound healing suggest that the involvement of COX-2 in gastric epithelial cell proliferation is not mediated solely by PGE2.
环氧化酶-2（COX-2）是花生四烯酸合成前列腺素的限速酶之一。虽然已知抑制环氧化酶活性会延迟溃疡愈合，但COX-2与其代谢产物在胃上皮细胞增殖中的调节关系尚不清楚。
研究COX-2是否对胃黏膜细胞增殖有影响，并进一步研究这种影响是否仅由胃黏膜中花生四具有代表性的花生四烯酸代谢产物前列腺素E2（PGE2）介导。
在添加花生四烯酸或COX-2选择性抑制剂JTE522的情况下，在分离的大鼠胃上皮细胞和大鼠胃细胞系RGM1的完整单层细胞片上制造特定面积大小的人工伤口。通过监测伤口大小评估伤口修复情况，使用5-溴脱氧尿苷染色检测细胞增殖。采用酶免疫测定法测量分泌的PGE2量。
胎牛血清刺激增加了COX-2蛋白的表达，抑制COX-2会延迟伤口愈合并减少细胞增殖。花生四烯酸增加了PGE2的产生并加速了修复。与对照组相比，JTE522和花生四烯酸联合使用导致伤口愈合明显延迟，但JTE522并未完全抑制添加花生四烯酸后细胞PGE2含量的增加。
JTE522对PGE2产生和伤口愈合的影响差异表明，COX-2参与胃上皮细胞增殖并非仅由PGE2介导。
