Liver ischemia/reperfusion (IR) injury is typified by an inflammatory response. Understanding the cellular and molecular events underpinning this inflammation is fundamental to developing therapeutic strategies. Great strides have been made in this respect recently. Liver IR involves a complex web of interactions between the various cellular and humoral contributors to the inflammatory response. Kupffer cells, CD4þ lymphocytes, neutrophils, and hepatocytes are central cellular players. Various cytokines, chemokines, and complement proteins form the communication system between the cellular components. The contribution of the danger-associated molecular patterns and pattern recognition receptors to the pathophysiology of liver IR injury are slowly being elucidated. Our knowledge on the role of mitochondria in generating reactive oxygen and nitrogen species, in contributing to ionic disturbances, and in initiating the mitochondrial permeability transition with subsequent cellular death in liver IR injury is continuously being expanded. Here, we discuss recent findings pertaining to the aforementioned factors of liver IR, and we highlight areas with gaps in our knowledge, necessitating further research. Liver Ischemia/reperfusion (IR) injury results from a prolonged ischemic insult followed by restoration of blood perfusion. It affects all oxygen dependent cells that rely on an uninterrupted blood supply. These aerobic cells require mitochondrial oxidative phosphorylation for their energy supply. Consequently all aerobically metabolizing tissues and organs are potential targets of IR injury.

SUMMARY BackgroundBefore stopping nucleos(t)ide analogue (NA) treatment in chronic hepatitis B (CHB), 6-12 months of consolidation therapy is recommended.

Ischaemia reperfusion (IR) injury is a clinical entity with a major contribution to the morbidity and mortality of liver surgery and transplantation. A central pathway of protection against IR injury utilizes nitric oxide (NO). Nitric oxide synthase (NOS) enzymes manufacture NO from L-arginine. NO generated by the endothelial NOS (eNOS) isoform protects against liver IR injury, whereas inducible NOS (iNOS)-derived NO may have either a protective or a deleterious effect during the early phase of IR injury, depending on the length of ischaemia, length of reperfusion and experimental model. In late phase hepatic IR injury, iNOS-derived NO plays a protective role. In addition to NOS consumption of L-arginine during NO synthesis, this amino acid may also be metabolized by arginase, an enzyme whose release is increased during prolonged ischaemia, and therefore diverts L-arginine away from NOS metabolism leading to a drop in the rate of NO synthesis. NO most commonly acts through the soluble guanylyl cyclase-cyclic GMPprotein kinase G pathway to ameliorate hepatic IR injury. Both endogenously generated and exogenously administered NO donors protect against liver IR injury. The beneficial effects of NO on liver IR are not, however, universal, and certain conditions, such as steatosis, may influence the protective effects of NO. In this review, the evidence for, and mechanisms of these protective actions of NO are discussed, and areas in need of further research are highlighted.Hepatic ischaemia reperfusion (IR) injury can be identified either in interventional settings causing direct liver ischaemia such as liver surgery and transplantation or in the setting of systemic hypoxaemia (e.g. respiratory failure) or shock states followed by resuscitation (e.g. haemorrhage, sepsis). The consequences of liver IR injury are hepatocyte and sinusoidal endothelial cell (SEC) necrosis, apoptosis or a combination of both (1).Nitric oxide (NO) is a gas with a molecular mass of 30.0 daltons. It is a free radical due to the presence of an unpaired electron in its valence shell. This structural configuration results in NO being highly reactive, with a consequent half life in the order of 5-10 s. Numerous clinical and non-clinical benefits of NO are described in various organ systems. The effects of NO on liver IR may prove to be harmful, beneficial or a combination of both. The determining factors are the length of the ischaemic insult and the enzymatic source of NO. There are no previous comprehensive reviews that focus on the protective actions of NO in liver IR injury. This upto-date review begins with a discussion on the role of nitric oxide synthase and its substrate, L-arginine. Next, the effects of soluble guanylyl cyclase-cyclic GMP-protein kinase G pathway on liver IR injury are discussed. This is followed by a comprehensive summary of the mechanisms underlying the protective actions of endogenous and exogenous (NO donors) NO in warm and cold liver IR injury. Finally, the influence of NO on IR injury in steatotic livers ...