Divergent roles of superoxide and nitric oxide in liver ischemia and reperfusion injury

Abstract

Liver ischemia and reperfusion-induced injury is a major clinical complication associated with hemorrhagic or endotoxin shock and thermal injury as well as liver transplantation and resectional surgery. Data obtained from several different studies suggest that an important initiating event in the pathophysiology of ischemia and reperfusion-induced tissue injury is enhanced production of superoxide concomitant with a decrease in the bioavailability of endothelial cell-derived nitric oxide. This review will summarize the evidence supporting the hypothesis that the redox imbalance induced by alterations in superoxide and nitric oxide generation creates a more oxidative environment within the different cells of the liver that enhances the nuclear transcription factor-κB-dependent expression of a variety of different cytokines and mediators that may promote as well as limit ischemia and reperfusion-induced hepatocellular injury. In addition, the evidence implicating endothelial cell nitric oxide synthase-dependent and -independent generation of nitric oxide as important regulatory pathways that act to limit ischemia and reperfusion-induced liver injury and inflammation is also presented.

Keywords: NF-κB; cytokines; free radicals; nitrite; peroxynitrite.

Fig. 1

NF-κB-dependent injurious and protective responses induced by liver ischemia and reperfusion. Ischemia and reperfusion of the liver induces an increase in the production of superoxide and other reactive oxygen species that may directly or indirectly decrease in the bioavailability of NO. This redox imbalance generates a more oxidative environment within the Kupffer cells, hepatocytes and sinusoidal endothelial cells that is thought to promote NF-κB-dependent expression of injurious and protective mediators.

Fig. 2

Effect of SOD2/3 on ischemia and reperfusion-induced liver injury. Mice were treated with the fusion protein SOD2/3 (1,000 U/kg, iv) or vehicle 15 min prior to being subjected to 90 min of ischemia and 6 h of reperfusion. *: p<0.05 vs vehicle-treated mice controls. n≥6 animals per group. Reproduced from (3) with permission.

Fig. 3

Effect of eNOS deficiency on ischemia and reperfusion liver injury. eNOS deficient (eNOS^−/−) or wild type mice were subjected to 45 min of ischemia and 6 h of reperfusion. *: p<0.05 vs sham-operated mice; ^#: p<0.05 vs time matched wild type muse. n≥6 animals per group. Data reproduced from (3) with permission.

Fig. 4

Classical and Alternative Pathways for ischemia and reperfusion-induced activation of NF-κB. Derived from (39).

Fig. 5

Proposed cytoprotective mechanisms for eNOS- or nitrite (NO₂⁻)-derived nitric oxide (NO). NO derived from eNOS or NO₂⁻ may protect tissue subjected to ischemia and reperfusion by: a) Inactivation of caspase-3 via the NO-dependent S-nitrosation of the protein; b) cGMP/protein kinase G (cGMP/PKG)-mediated opening of mitochondrial ATP-dependent potassium channels (K_ATP) which reduces the loss of cytochrome C, decreases calcium accumulation within the mitochondria, prevent the opening of the mitochondrial permeablility transition (MPT) pore and decrease apoptosis; c) Inhibition of mitochondrial electron transport via the direct or indirect (S-nitrosation) inhibition of Complex I (and possible Complex IV) resulting in decreased reactive oxygen specie (ROS) generation, reduced cytochrome C release and decreased apoptosis.

Fig. 6

Proposed mechanisms for the conversion of nitrite (NO₂⁻) to nitric oxide (NO). P-Fe⁺² represents ferrous hemoglobin (Hb) or myoglobin (Mb). Mo⁺⁴ represents molybdenum at the active site of xanthine oxidase (XO); Asc and Ph-OH represent ascorbic acid and an aromatic phenolic compound, respectively. Figure derived from reference (66).