吲哚美辛诱导胃黏膜损伤中肿瘤坏死因子-α的产生及细胞凋亡：奥美拉唑和依罗替丁的作用

Induction of tumor necrosis factor-alpha and apoptosis in gastric mucosal injury by indomethacin: effect of omeprazole and ebrotidine.

作者信息

Slomiany B L, Piotrowski J, Slomiany A

机构信息

University of Medicine and Dentistry of New Jersey, Newark 07103-2400, USA.

出版信息

Scand J Gastroenterol. 1997 Jul;32(7):638-42. doi: 10.3109/00365529708996511.

DOI:10.3109/00365529708996511

PMID:9246701

Abstract

BACKGROUND

The gastric injury associated with nonsteroidal anti-inflammatory drug (NSAID) therapy has been linked to the detrimental effects of the agents on the processes of prostaglandin generation, leukocyte adherence, superoxides production, and mucosal cell proliferation. In the present study we investigated the expression of tumor necrosis factor-alpha (TNF-alpha) and epithelial cell apoptosis during indomethacin-induced gastric mucosal injury and evaluated the effect of two antiulcer agents on this process.

METHODS

The experiments were carried out with groups of rats subjected to intragastric pretreatment with 40 mg/kg omeprazole, 100 mg/kg ebrotidine, or vehicle, followed 30 min later by an intragastric dose of indomethacin at 60 mg/kg. After 2 h the animals were killed, and the gastric mucosal tissue used for macroscopic damage assessment, quantitation of TNF-alpha expression, and the assay of epithelial cell apoptosis.

RESULTS

In the absence of antiulcer drugs, indomethacin caused extensive multiple hemorrhagic lesions accompanied by a 47% increase in mucosal expression of TNF-alpha and a dramatic (> 300-fold) enhancement in gastric epithelial cell apoptosis. Pretreatment with a proton pump inhibitor, omeprazole, produced only marginal (6-8%) reduction in the extent of mucosal damage caused by indomethacin, whereas the mucosal expression of TNF-alpha decreased by 15% and the apoptotic DNA fragmentation by 10-13%. In contrast, the H2-receptor antagonist ebrotidine, also known for its gastroprotective effects, not only successfully prevented (98.3%) the enhancement in mucosal TNF-alpha expression caused by indomethacin but also caused a 54% reduction in the epithelial cell apoptosis. These effects of ebrotidine were, furthermore, reflected in a 90.2% prevention in the gastric mucosal damage.

CONCLUSIONS

Our findings provide new insights into the mechanism of gastric injury caused by NSAIDs and show that ebrotidine protection against indomethacin-induced mucosal damage occurs through the inhibition of epithelial cell apoptosis triggered by the enhancement in the mucosal TNF-alpha expression. Our data also show that omeprazole does not possess antiapoptotic properties.

摘要

背景

与非甾体抗炎药（NSAID）治疗相关的胃损伤与这些药物对前列腺素生成、白细胞黏附、超氧化物产生及黏膜细胞增殖过程的有害影响有关。在本研究中，我们调查了吲哚美辛诱导胃黏膜损伤过程中肿瘤坏死因子-α（TNF-α）的表达及上皮细胞凋亡情况，并评估了两种抗溃疡药物在此过程中的作用。

方法

实验用大鼠分组，分别给予40mg/kg奥美拉唑、100mg/kg依罗替丁或赋形剂进行胃内预处理，30分钟后再给予60mg/kg吲哚美辛胃内给药。2小时后处死动物，取胃黏膜组织进行大体损伤评估、TNF-α表达定量及上皮细胞凋亡检测。

结果

在无抗溃疡药物时，吲哚美辛导致广泛的多发性出血性损伤，同时黏膜TNF-α表达增加47%，胃上皮细胞凋亡显著增强（>300倍）。质子泵抑制剂奥美拉唑预处理仅使吲哚美辛所致黏膜损伤程度略有降低（6-8%），而黏膜TNF-α表达降低15%，凋亡DNA片段化降低10-13%。相比之下，同样具有胃保护作用的H2受体拮抗剂依罗替丁不仅成功预防了（98.3%）吲哚美辛所致黏膜TNF-α表达增强，还使上皮细胞凋亡减少54%。依罗替丁的这些作用还体现在胃黏膜损伤预防率达90.2%。