Hepatic ischemia reperfusion injury: pathogenic mechanisms and basis for hepatoprotection

J Gastroenterol Hepatol. 2003 Aug;18(8):891-902. doi: 10.1046/j.1440-1746.2003.03056.x.


This review highlights recent advances in our understanding of mechanisms underlying reperfusion injury to the liver after warm hepatic ischemia. Sinusoidal endothelial cells and hepatocytes are targets of injury in the early 'cytotoxic' phase, although participation of apoptosis in the cell-death process remains contentious. Kupffer cells may play an important role as the initial cytotoxic cell type and are likely a source of reactive oxygen species and proinflammatory mediators, particularly tumor necrosis factor (TNF)-alpha. The latter are involved with subsequent neutrophil activation and recruitment. Microcirculatory disruption results from an imbalance between the actions of vasoconstrictors and vasodilators, such as nitric oxide, and also has a major impact on reperfusion injury. There is growing evidence that a brief prior ischemia-reperfusion period, termed 'ischemic preconditioning', is hepatoprotective. This can be mimicked by drugs that produce oxidative stress, and by interleukin-6 and TNF-alpha; both these cytokines are involved with priming hepatocytes to enter the cell cycle. Several mechanisms have been implicated including mobilization of adenosine and activation of adenosine type 2 receptors, nitric oxide, abrogation of TNF synthesis, preservation of energy metabolism, protection of the microcirculation and accelerated cell-cycle entry. A better understanding of preconditioning mechanisms will lead to novel approaches to improve outcomes of liver surgery.

Publication types

  • Review

MeSH terms

  • Adenosine / metabolism
  • Animals
  • Apoptosis / physiology
  • Cell Adhesion Molecules / metabolism
  • Hepatocytes / pathology*
  • Humans
  • Hydrogen-Ion Concentration
  • Interleukin-1 / metabolism
  • Interleukin-6 / metabolism
  • Ischemic Preconditioning
  • Kupffer Cells / pathology*
  • Liver / cytology*
  • Liver / pathology*
  • Liver Circulation
  • Microcirculation
  • Nitric Oxide / metabolism
  • Reactive Oxygen Species / metabolism
  • Reperfusion Injury / physiopathology*
  • Reperfusion Injury / prevention & control
  • Tumor Necrosis Factor-alpha / metabolism
  • Warm Ischemia*


  • Cell Adhesion Molecules
  • Interleukin-1
  • Interleukin-6
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Adenosine