Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content +++ CLINICAL IMPACT ++ Ischemia-reperfusion (I/R) injury is a technically unavoidable complication of transplantation. It has been implicated as an important etiologic factor in the pathogenesis of acute and chronic graft failure in up to 30% of liver transplants.1 The use of extended-criteria organs amplifies the problem with liver I/R, as many of these organs are more susceptible to the consequences of I/R, including steatotic donor livers and livers with prolonged ischemic time.2 +++ PATHOPHYSIOLOGY ++ The cessation of blood flow has multiple effects on an organ. The primary consequences are decreased oxygen delivery (hypoxia) and decreased clearance of toxic metabolites. Hypoxia is the major culprit in ischemic liver injury. A study of isolated rat livers suggests that the extent of liver injury occurring due to ischemia can be replicated by the perfusion of hypoxic blood.3 Hypoxia results in the depletion of adenosine triphosphate (ATP), which is required to sustain multiple cellular processes, including: Maintenance of Na+/K+ pumps Protein synthesis and degradation DNA/RNA synthesis ATP levels continue to be adversely affected after reperfusion due to mitochondrial injury, as demonstrated by a decrease in mitochondrial mass and activity. Depending on the original insult, these effects on the mitochondria can persist late into reperfusion. Mitochondria are also a major contributor to oxidative injury occurring during I/R. Sterile inflammation is another characteristic feature of I/R injury, and this is primarily attributed to actions of the innate immune system. Neutrophil-mediated oxidative injury is the most prominent deleterious process during the inflammatory phase of hepatic I/R injury. Damage-associated molecular patterns (DAMPs) are released by injured hepatocytes after I/R. Examples of DAMPs include mitochondrial DNA, high-mobility protein group B1 (HMGB1), and cold-inducible RNA-binding protein (CIRP). DAMPs are recognized by pattern recognition receptors (PRRs) on innate immune cells. Examples of PRRs include toll-like receptors (TLRs), nucleotide oligomerization domain-like receptors (NLRs), and retinoic acid–inducible gene I-like receptors (RLRs). TLR 4 is a PRR that has been shown to contribute to the pathogenesis of hepatic I/R injury. In addition to the effects of the innate immune response, there is growing evidence to support a proinflammatory adaptive immune response in I/R injury, with CD4 T cells playing a key role.4 Several protective mechanisms are also activated during I/R. The activation of the autophagy salvage pathway has been demonstrated after I/R injury. Autophagy targets dysfunctional organelles and large macromolecules for lysosomal degradation. It does this while also generating energy, thereby possibly diminishing the existent energy deficit. The inflammatory response has also been implicated in the regenerative process necessary for healing after I/R. +++ CLINICAL TRIALS ++ Perhaps the most studied clinical intervention postulated to have a beneficial impact on ischemic injury is ischemic preconditioning (IP). IP involves clamping the vascular supply to an organ for short periods prior to an anticipated ischemic event. The use of IP has been limited in transplantation due to the associated ... Your Access profile is currently affiliated with '[InstitutionA]' and is in the process of switching affiliations to '[InstitutionB]'. Please click ‘Continue’ to continue the affiliation switch, otherwise click ‘Cancel’ to cancel signing in. Get Free Access Through Your Institution Learn how to see if your library subscribes to McGraw Hill Medical products. Subscribe: Institutional or Individual Sign In Username Error: Please enter User Name Password Error: Please enter Password Forgot Password? Forgot Username? Sign in via OpenAthens Sign in via Shibboleth You already have access! Please proceed to your institution's subscription. Create a free a profile for additional features.