Zhang Yi-Ping, Liu Xin-Ran, Yang Mei-Wen, Yang Shu-Long, Hong Fen-Fang
Experimental Center of Pathogen Biology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China.
Department of Surgery, Fuzhou Medical College, Nanchang University, Fuzhou 344000, Jiangxi Province, China.
World J Hepatol. 2022 Mar 27;14(3):504-515. doi: 10.4254/wjh.v14.i3.504.
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.
肝缺血再灌注损伤（HIRI）是肝脏手术和移植中发病率和死亡率的主要临床原因。许多研究发现，一氧化氮（NO）在HIRI中起重要作用，其增加或减少会影响HIRI的进展和结果。然而，NO在HIRI中的作用存在争议且复杂。内皮型一氧化氮合酶（eNOS）产生的NO在HIRI中起保护作用，而诱导型一氧化氮合酶（iNOS）产生的过量NO会加速炎症并增加氧化应激，进一步加重HIRI。尽管如此，eNOS的过度表达可能会加剧HIRI，而在某些情况下iNOS产生的NO会减轻HIRI。在此，我们综述了对NO在HIRI中作用的新认识进展：（1）NO通过增加NO生物利用度、下调白三烯C4合酶、抑制核因子κB（NFκB）途径的激活、增强细胞自噬以及减少炎性细胞因子和活性氧（ROS），在HIRI中发挥不同作用。并且NO通过调节凋亡因子具有保护和有害双重作用；（2）eNOS促进NO生成并抑制其自身过度表达，从而发挥反向肝保护作用。其激活受PI3K/Akt和KLF2/AMPK途径调节；（3）iNOS产生的NO主要对HIRI有恶化作用，而在某些条件下可能具有保护功能。它们的表达应达到平衡以减少不良影响并使NO在HIRI治疗中具有保护作用。因此，可以推断，NO调节药物可能是治疗HIRI的新方向，或者可作为减轻HIRI以保护肝脏的辅助药物。
