雷贝拉唑对非甾体抗炎药诱导小肠损伤的保护作用及可能机制研究

Protective effect of rabeprazole on indomethacin-induced small intestinal injury and its possible mechanism

目的探讨质子泵抑制剂（PPIs）药物雷贝拉唑对非甾体抗炎药（NISADs）吲哚美辛诱导小肠损伤的保护作用及可能机制。方法检测PPIs雷贝拉唑对吲哚美辛诱导小肠损伤的保护作用及与HO-1的相关性。给予小鼠口服吲哚美辛10 mg/kg,24 h后处死。在给予吲哚美辛前30 min,口服雷贝拉唑30~100 mg/kg和奥美拉唑30~100 mg/kg;在给予吲哚美辛或雷贝拉唑前10 min,肌内注射HO-1抑制剂锡-原卟啉（Sn PP）30 mg/kg。结果吲哚美辛引起小肠出血性损伤,侵袭性肠道杆菌数量增加,诱导型一氧化氮合酶（i NOS）表达和髓过氧化物酶（MPO）活性增加。雷贝拉唑以剂量依赖性保护吲哚美辛引起的肠损伤,并且MPO活性上升受到抑制,而奥美拉唑无该作用。预处理Sn PP能够加重吲哚美辛引起的小肠损伤,并拮抗雷贝拉唑的保护作用。结论雷贝拉唑能够保护吲哚美辛诱导的小肠损伤,并与雷贝拉唑通过上调黏膜中HO-1/CO的表达而抑制i NOS表达。

[Objective ] To examine the effect of proton pump inhibitors （PPIs） such as rabeprazole and omeprazole on indomethacin-induced small intestinal lesions in mice and its possible mechanism. [Methods] The effect of rabeprazole, a PPI, on indomethacin-induced small intestinal ulceration was examined in mice, particularly its relation to heme oxygenase （HO）-I was analyzed. The mice were administered indomethacin （10 mg/kg, p.o.） and killed 24 h later. Rabeprazole （30-100 mg/kg, p.o.） and omeprazole （30-100 mg/kg, p.o.） were given 30 min before the administration of indomethacin, while tin-protoporphyrin IX （SnPP： 30 mg/kg, i.m.）, an inhibitor of HO-1, was injected 10 min before indomethacin or rabeprazole administration. [Results] Indomethacin produced hemorrhagic lesions in the small intestine, accompanied with increases in mucosal invasion of enterobacteria, inducible nitric oxide synthase （iNOS） expression and myeloperoxidase （MPO） activity in the mucosa. Pretreatment with rabeprazole dose-dependently reduced the severity of the indomethacin-induced intestinal lesions, with suppression of the increased MPO activity, while omeprazole did not have such effects. Pretreatment with SnPP significantly exacerbated these intestinal lesions and almost totally abolished the protective effect of rabeprazole. [Conclusions] Rabeprazole prevents indomethacin-induced small intestinal ulceration, and this effect is associated with inhibition of iNOS expression through up-regulation of HO-1/CO production in the mucosa.