Dexmedetomidine Attenuates Orthotopic Liver Transplantation-Induced Acute Gut Injury via α 2-Adrenergic Receptor-Dependent Suppression of Oxidative Stress.

Peibiao Lv,Tufeng Chen,Fan Tan,Jun Cai,Yingqing Deng,Xinjin Chi,Peibin Liu,Jun Li,Jiaxin Chen,Jingling Tian,Lei Zheng

doi:10.1155/2019/9426368

Abstract

Patients with orthotopic liver transplantation (OLT) frequently develop acute gut injury (AGI), and dexmedetomidine (Dex) has been reported to exert a protective effect against AGI. We investigated whether Dex protects against AGI through antioxidative stress effects by the Nrf2/HO-1 antioxidative signaling pathway. Rats were randomly allocated into a sham group and six orthotopic autologous liver transplantation (OALT) groups receiving different doses of Dex together with/without α2-adrenergic receptor (AR) blockers. Intestinal tissues were collected to visualize the barrier damage and to measure the indexes of oxidative stress. For in vitro studies, rat intestinal recess epithelial cells (IEC-6) underwent hypoxia/reoxygenation (H/R), and the protective role of Dex was evaluated after α2A-AR siRNA silencing. OALT resulted in increased oxidative stress, significant intestinal injury, and barrier dysfunction. Dex attenuated OALT-induced oxidative stress and intestinal injury, which was abolished by the pretreatment with the nonspecific α2A-AR siRNA blocker atipamezole and the specific α2A-AR siRNA blocker BRL-44408, but not by the specific 2B/C-AR siRNA blocker ARC239. Silencing of α2A-AR siRNA also attenuated the protective role of Dex on alleviating oxidative stress in IEC-6 cells subjected to H/R. Dex exerted its protective effects by activating Nrf2/HO-1 antioxidative signaling. Collectively, Dex attenuates OALT-induced AGI via α2A-AR-dependent suppression of oxidative stress, which might be a novel potential therapeutic target for OALT-induced AGI.

Highlights

Orthotopic liver transplantation (OLT) is considered to be the best treatment for patients with end-stage liver diseases [1]
Since nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that exhibits an antioxidative effect by increasing the levels of antioxidants, such as superoxide dismutase (SOD) and CAT, we investigated whether Dex exerts its effects through the Nrf2/HO-1 signaling pathway
We demonstrated that pretreatment of rats with Dex dose-dependently reduced injury of the intestinal mucosal barrier during orthotopic autologous liver transplantation (OALT)-induced acute gut injury (AGI)

Summary

Introduction

Orthotopic liver transplantation (OLT) is considered to be the best treatment for patients with end-stage liver diseases [1]. Inferior vena cava occlusion during OLT can induce stasis of the inferior and superior mesenteric veins, which often results in acute gut injury (AGI). Manifested by intercellular tight junction dysfunction and destruction of intestinal barriers, AGI is a life-threatening condition with a disastrous prognosis [2]. Intestinal injury contributes to a high mortality rate due to injury-associated bacterial translocation, oxidative stress, inflammatory response, and eventual multiple organ dysfunction [3, 4]. Intestinal epithelial cell protection is considered to be crucial for patients undergoing liver transplantation, the detailed mechanisms responsible for OLT-induced AGI remain largely unknown. There is no effective treatment strategy to combat intestinal ischemia/reperfusion (IR) injury following OLT

Methods

Results

Conclusion