New progress in roles of nitric oxide during hepatic ischemia reperfusion injury

Abstract

Hepatic ischemia reperfusion injury (HIRI) is a clinical condition which may lead to cellular injury and organ dysfunction. The role of nitric oxide (NO) in HIRI is complicated and inconclusive. NO produced by endothelial nitric oxide synthase (eNOS) activation plays a protective role during early HIRI. But eNOS overexpression and the resulting excessive NO bioavailability can aggravate liver injury. NO induced by inducible nitric oxide synthase (iNOS) may have either a protective or a deleterious effect during the early phase of HIRI, but it may protect the liver during late HIRI. Here, we reviewed the latest findings on the role of NO during HIRI: (1) NO exerts a protective effect against HIRI by increasing NO bioavailability, downregulating p53 gene expression, decreasing inflammatory chemokines, reducing ROS via inhibiting the mitochondrial respiratory chain, activating sGC-GTP-cGMP signal pathway to reduce liver cell apoptosis, and regulating hepatic immune functions; (2) eNOS protects against HIRI by increasing NO levels, several eNOS/NO signal pathways (such as Akt-eNOS/NO, AMPK-eNOS/NO and HIF-1α-eNOS/NO) participating in the anti-HIRI process, and inhibiting over-expression of eNOS also protects against HIRI; and (3) the inhibition of iNOS prevents HIRI. Thus, the adverse effects of NO should be avoided, but its positive effect in the clinical treatment of diseases associated with HIRI should be recognized.

LDL dinitrosyl iron complex: A new transferrin‐independent route for iron delivery in hepatocytes

“…High iron contents and NO production in activated macrophages may lead to formation of electron paramagnetic resonance (EPR)‐detectable dinitrosyl iron complexes (DNICs) . On the other hand, NO microcirculation and elevated levels of NO were observed in liver injury, the condition of the high iron demand due to the enhanced cell proliferation, and were found beneficial for improved allograft function after transplantation . High Fe and LDL contents coincide also in normal hepatocytes due to the fundamental functions of liver, which are lipid metabolism and iron storage .…”

Ischemic postconditioning decreases iNOS gene expression but ischemic preconditioning ameliorates histological injury in a swine model of extended liver resection

“…To date, only few studies have advocated independently the protective role on the hepatocyte of either preconditioning (30) or postconditioning (26,27) in both animal models and humans (39); however none has compared directly the effect of pre-to postconditioning. Furthermore, recent studies have concluded that during I/R injury there is over expression of iNOS and/or eNOS and their inhibition protects from I/R injury (40), therefore pointing towards a fine balance between beneficial and detrimental effects of the bioavailability of NO.…”

Hydrogen Sulfide as a Novel Regulatory Factor in Liver Health and Disease

“…Under different pathological conditions, hepatic I/R injury can be classified into warm and cold I/R injury according to the environmental temperature [115]. It is well known that hepatic I/R injury involves several mechanisms, including pH imbalance, calcium overload, mitochondrial dysfunction, ROS overproduction, anaerobic metabolism, activation of Kupffer cells and neutrophils, and the production of cytokines and chemokines [113, 114, 116, 117]. Despite significant improvements in surgical techniques and perioperative care, therapies to suppress hepatic I/R injury at the bedside remain limited largely due to the complex mechanisms [118].…”