Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 7, 2014; 20(41): 15289-15298
Published online Nov 7, 2014. doi: 10.3748/wjg.v20.i41.15289
N-acetylcysteine attenuates reactive-oxygen-species-mediated endoplasmic reticulum stress during liver ischemia-reperfusion injury
Yong Sun, Li-Yong Pu, Ling Lu, Xue-Hao Wang, Feng Zhang, Jian-Hua Rao
Yong Sun, Department of General Surgery, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
Yong Sun, Li-Yong Pu, Ling Lu, Xue-Hao Wang, Feng Zhang, Jian-Hua Rao, Key Laboratory of Living Donor Liver Transplantation of Chinese Ministry of Health, Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Author contributions: Sun Y and Pu LY contributed equally to this work; Sun Y, Pu LY, Zhang F and Rao JH contributed to conception and design; Sun Y, Lu L and Rao JH contributed to the data analysis and interpretation; Sun Y, Pu LY and Rao JH contributed to the data collection; Lu L, Wang XH and Rao JH contributed to the manuscript preparation; Sun Y, Lu L, Zhang F and Rao JH contributed to the critical revision of the article.
Supported by First Affiliated Hospital of Nanjing Medical University and the National Natural Science Foundation of China, Grant No. 81100270, No. 81070380, No. 81310108001, No. 81210108017 and No.81273261
Correspondence to: Feng Zhang, MD, PhD, Key Laboratory of Living Donor Liver Transplantation of Chinese Ministry of Health, Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, China. zhangf@njmu.edu.cn
Telephone: +86-25-83718836 Fax: +86-25-83672106
Received: February 11, 2013
Revised: April 8, 2014
Accepted: June 26, 2014
Published online: November 7, 2014
Processing time: 272 Days and 4.1 Hours
Abstract

AIM: To investigate the effects of N-acetylcysteine (NAC) on endoplasmic reticulum (ER) stress and tissue injury during liver ischemia reperfusion injury (IRI).

METHODS: Mice were injected with NAC (300 mg/kg) intraperitoneally 2 h before ischemia. Real-time polymerase chain reaction and western blotting determined ER stress molecules (GRP78, ATF4 and CHOP). To analyze the role of NAC in reactive oxygen species (ROS)-mediated ER stress and apoptosis, lactate dehydrogenase (LDH) was examined in cultured hepatocytes treated by H2O2 or thapsigargin (TG).

RESULTS: NAC treatment significantly reduced the level of ROS and attenuated ROS-induced liver injury after IRI, based on glutathione, malondialdehyde, serum alanine aminotransferase levels, and histopathology. ROS-mediated ER stress was significantly inhibited in NAC-treated mice. In addition, NAC treatment significantly reduced caspase-3 activity and apoptosis after reperfusion, which correlated with the protein expression of Bcl-2 and Bcl-xl. Similarly, NAC treatment significantly inhibited LDH release from hepatocytes treated by H2O2 or TG.

CONCLUSION: This study provides new evidence for the protective effects of NAC treatment on hepatocytes during IRI. Through inhibition of ROS-mediated ER stress, NAC may be critical to inhibit the ER-stress-related apoptosis pathway.

Keywords: N-acetylcysteine; Reactive oxygen species; Endoplasmic reticulum stress; Apoptosis; Liver ischemia-reperfusion

Core tip: The protective effect of N-acetylcysteine (NAC) treatment has been confirmed in IRI; however, its underlying mechanism remains unclear. Our previous data showed that endoplasmic reticulum (ER) stress is critical for the development of liver IRI. We have found new evidence for the protective effects of NAC on hepatocytes during liver IRI. Our data demonstrated that NAC modulates ER stress signaling and reduces ER-stress-mediated apoptosis during liver IRI. These findings provide further support for the usefulness of exploring NAC as a potential alternative drug for treating liver IRI.