Luo Jiing C, Shin Vivian Y, Liu Edgar S L, So Wallace H L, Ye Yi N, Chang Full Y, Cho Chi H
Department of Pharmacology, Faculty of Medicine, 2nd Floor, Laboratory Block, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
J Pharmacol Exp Ther. 2003 Nov;307(2):692-8. doi: 10.1124/jpet.103.055202. Epub 2003 Sep 9.
Although the ulcerogenic action of corticosteroids in the stomach is controversial, its action on ulcer healing has not been defined. In this study, we used non-ulcerogenic doses of dexamethasone (0.1 or 0.2 mg/kg/day) to explore the adverse effect on ulcer healing as well as its pathological mechanisms in rat stomach. In this regard, we measured ulcer size, mucus thickness, epithelial cell proliferation and apoptosis, and angiogenesis at the ulcer site at different time points after ulcer induction. Protein expressions of cyclooxygenase-1 and -2 (COX-1 and COX-2) and cytosolic phospholipase A2 (cPLA2) over the ulcer margin were evaluated, and the mucosal prostaglandin E2 (PGE2) level was also determined. Dexamethasone treatment in the current doses did not produce mucosal damage in intact animals. However, the drug dose-dependently delayed gastric ulcer healing. It also decreased mucus content and epithelial cell proliferation at the ulcer margin as well as angiogenesis at the ulcer margin and base. These were associated with a significant decrease of COX-2 expression and PGE2 level but not COX-1 at the ulcer margin. The drug only marginally reduced the cPLA2 expression without affecting the apoptosis at the ulcer margin. PGE2 treatment reversed the adverse effects of dexamethasone on ulcer healing. It is concluded that nonulcerogenic doses of dexamethasone can delay ulcer repair via depression of COX-2 expression and PGE2 formation in the gastric mucosa.
尽管皮质类固醇在胃中的致溃疡作用存在争议，但其对溃疡愈合的作用尚未明确。在本研究中，我们使用非致溃疡剂量的地塞米松（0.1或0.2毫克/千克/天）来探讨其对大鼠胃溃疡愈合的不良影响及其病理机制。在这方面，我们在溃疡诱导后的不同时间点测量了溃疡大小、黏液厚度、上皮细胞增殖和凋亡以及溃疡部位的血管生成。评估了溃疡边缘环氧化酶-1和-2（COX-1和COX-2）以及胞质磷脂酶A2（cPLA2）的蛋白表达，并测定了黏膜前列腺素E2（PGE2）水平。当前剂量的地塞米松处理在完整动物中未产生黏膜损伤。然而，该药物剂量依赖性地延迟了胃溃疡的愈合。它还降低了溃疡边缘的黏液含量、上皮细胞增殖以及溃疡边缘和底部的血管生成。这些与溃疡边缘COX-2表达和PGE2水平的显著降低有关，但与COX-1无关。该药物仅轻微降低了cPLA2表达，而不影响溃疡边缘的细胞凋亡。PGE2处理逆转了地塞米松对溃疡愈合的不良影响。结论是，非致溃疡剂量的地塞米松可通过抑制胃黏膜中COX-2表达和PGE2形成来延迟溃疡修复。
