Xie Wei, Huang Xielin, Chen Renpin, Chen Ruru, Li Tang, Wu Wei, Huang Zhiming
Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Drug Des Devel Ther. 2019 Aug 22;13:2969-2984. doi: 10.2147/DDDT.S193641. eCollection 2019.
Stress ulcer is a severe complication in critically ill patients and causes a high mortality. The proton pump inhibitor esomeprazole is widely applied in the treatment of stress ulcers because of its powerful acid suppression ability. However, the mechanism of stress ulcer and the precise gastroprotective effect of esomeprazole in stress ulcer remain unclear.
In the present study, the rats with water-immersed and restraint (WIR)-induced stress ulcer were used to further elucidate the anti-ulcerogenic capacity of esomeprazole in stress ulcer in addition to its anti-acid secreting ability.
The rats were randomly divided into 5 groups: control group (NS), water-immersed and restraint group (WIR), high-dose application of esomeprazole plus stress ulcer-induced group (HE+WIR), low-dose application of esomeprazole plus stress ulcer-induced group (LE+WIR), and high-dose application of esomeprazole without stress ulcer-induced group (HE). Our study showed that the pretreatment of esomeprazole alleviated gastric tissue damage in both macroscopic and histopathological manifestations. Pretreatment of esomeprazole elevated the decline in PEG2 level affected by WIR; and it inhibited the secretion of gastric acid, gastrin and pepsin. Moreover, esomeprazole exerted its antioxidant effects by reducing malondialdehyde levels, enhancing the expressions of antioxidant factors like glutathione and superoxide dismutase (SOD) and reducing the compensatory transcriptional elevation of SOD1 gene. Esomeprazole also reduced the levels of MPO (myeloperoxidase), tumor necrosis factor (TNF)-α and interleukin (IL)-1β according to its anti-inflammatory effects. We further explored the possible mechanism of esomeprazole pretreatment on stress ulcer and demonstrated that esomeprazole attenuated the high phosphorylation levels of nuclear factor kappa B (NF-κB) p65 and p38 MAPK, and decreased the NF-κB p65 nuclear translocation induced by WIR related stress ulcer.
Our study provides some evidence that the esomeprazole pretreatment exerts gastroprotective effects in WIR-induced stress ulcer through not only its antisecretory effect but also its antioxidant effect by inactivating the p38 MAPK and NF-κB signaling pathways.
应激性溃疡是危重症患者的一种严重并发症，死亡率很高。质子泵抑制剂埃索美拉唑因其强大的抑酸能力而广泛应用于应激性溃疡的治疗。然而，应激性溃疡的发病机制以及埃索美拉唑在应激性溃疡中确切的胃保护作用仍不清楚。
在本研究中，采用水浸束缚（WIR）诱导的应激性溃疡大鼠，除了研究埃索美拉唑的抑酸分泌能力外，进一步阐明其在应激性溃疡中的抗溃疡能力。
将大鼠随机分为5组：对照组（NS）、水浸束缚组（WIR）、高剂量埃索美拉唑加应激性溃疡诱导组（HE+WIR）、低剂量埃索美拉唑加应激性溃疡诱导组（LE+WIR）、高剂量埃索美拉唑无应激性溃疡诱导组（HE）。我们的研究表明，埃索美拉唑预处理在宏观和组织病理学表现上均减轻了胃组织损伤。埃索美拉唑预处理提高了受WIR影响的PEG2水平的下降；并抑制了胃酸、胃泌素和胃蛋白酶的分泌。此外，埃索美拉唑通过降低丙二醛水平、增强谷胱甘肽和超氧化物歧化酶（SOD）等抗氧化因子的表达以及降低SOD1基因的代偿性转录升高发挥抗氧化作用。埃索美拉唑还根据其抗炎作用降低了髓过氧化物酶（MPO）、肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β的水平。我们进一步探讨了埃索美拉唑预处理应激性溃疡的可能机制，证明埃索美拉唑减弱了核因子κB（NF-κB）p65和p38丝裂原活化蛋白激酶（MAPK）的高磷酸化水平，并减少了WIR相关应激性溃疡诱导的NF-κB p65核转位。
我们的研究提供了一些证据，表明埃索美拉唑预处理通过其抗分泌作用以及通过使p38 MAPK和NF-κB信号通路失活发挥抗氧化作用，从而在WIR诱导的应激性溃疡中发挥胃保护作用。
