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World J Hepatol. Mar 27, 2022; 14(3): 504-515
Published online Mar 27, 2022. doi: 10.4254/wjh.v14.i3.504
New progress in understanding roles of nitric oxide during hepatic ischemia-reperfusion injury
Yi-Ping Zhang, Xin-Ran Liu, Mei-Wen Yang, Shu-Long Yang, Fen-Fang Hong
Yi-Ping Zhang, Xin-Ran Liu, Fen-Fang Hong, Experimental Center of Pathogen Biology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
Mei-Wen Yang, Department of Surgery, Fuzhou Medical College, Nanchang University, Fuzhou 344000, Jiangxi Province, China
Shu-Long Yang, Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
Shu-Long Yang, Department of Physiology, Fuzhou Medical College, Nanchang University, Fuzhou 344000, Jiangxi Province, China
Author contributions: Zhang YP and Liu XR are co-first authors and contributed equally to this work, and they wrote and revised the paper; Yang MW participated in data collection and revised the paper by making point-by-point responses to the reviewers; Yang SL and Hong FF are co-corresponding authors who contributed equally to this work, and they are responsible for improving grammars and languages, conceptualizing the idea, and obtaining funding.
Conflict-of-interest statement: There is no conflict of interest associated with any of the authors or other coauthors in this manuscript.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Fen-Fang Hong, MD, Associate Professor, Experimental Center of Pathogen Biology, College of Medicine, Nanchang University, No. 461 Bayi Road, Nanchang 330006, Jiangxi Province, China. hongfenfang@126.com
Received: March 29, 2021
Peer-review started: March 29, 2021
First decision: June 15, 2021
Revised: July 9, 2021
Accepted: February 19, 2022
Article in press: February 19, 2022
Published online: March 27, 2022
Processing time: 360 Days and 4.8 Hours
Abstract

Hepatic ischemia-reperfusion injury (HIRI) is a major clinical cause of morbidity and mortality in liver surgery and transplantation. Many studies have found that nitric oxide (NO) plays an important role in the HIRI and its increase or decrease can affect the progression and outcome of HIRI. However, the role of NO in HIRI is controversial and complicated. NO derived by endothelial NO synthase (eNOS) shows a protective role in HIRI, while excessive NO derived by inducible NO synthase (iNOS) accelerates inflammation and increases oxidative stress, further aggravating HIRI. Nevertheless, the overexpression of eNOS may exacerbate HIRI and iNOS-derived NO in some cases reduces HIRI. Here we review the new progress in the understanding of the roles of NO during HIRI: (1) NO possesses different roles in HIRI by increasing NO bioavailability, down-regulating leukotriene C4 synthase, inhibiting the activation of the nuclear factorκB (NFκB) pathway, enhancing cell autophagy, and reducing inflammatory cytokines and reactive oxygen species (ROS). And NO has both protective and deleterious effects by regulating apoptotic factors; (2) eNOS promotes NO production and suppresses its own overexpression, exerting a hepatoprotective effect reversely. Its activation is regulated by the PI3K/Akt and KLF2/AMPK pathways; and (3) iNOS derived NO mainly has deteriorating effects on HIRI, while it may have a protective function under some conditions. Their expression should reach a balance to reduce the adverse side and make NO protective in the treatment of HIRI. Thus, it can be inferred that NO modulating drugs may be a new direction in the treatment of HIRI or may be used as an adjunct to mitigate HIRI for the purpose of protecting the liver.

Keywords: Hepatic ischemia-reperfusion injury; Nitric oxide; Endothelial nitric oxide synthase; Inducible nitric oxide synthase

Core Tip: This review focuses on the new progress in the understanding of the role of nitric oxide (NO) in hepatic ischemia-reperfusion injury (HIRI). NO protects HIRI by increasing NO bioavailability and cellular autophagy, down-regulating leukotriene C4 synthase, inhibiting the nuclear factor κB (NF-κB) pathway, and reducing inflammatory cytokines and reactive oxygen species. While by regulating apoptotic factors, it has dual effects. eNOS exerts hepatoprotective effects by promoting NO production through the involvement of the phosphoinositide 3-kinase/Akt pathway and Kruppel-like factor 2/adenosine monophosphate-activated protein kinase pathways. The function of eNOS overexpression remains controversial. iNOS-derived NO mainly deteriorates HIRI, but it may reduce damage under certain conditions. The balance of eNOS and iNOS is important for the HIRI protection.