Basic Mechanisms of Ischemia/Reperfusion Injury Leading to Cellular and Tissue Damage: Therapeutic Implications

  • Emmanuel E. Douzinas
  • Aikaterini Apeiranthitis


Produced free radicals exert their physiological function and thereafter become neutralized by antioxidants. In contrast, if they are produced in abundance, e.g., during ischemia/reperfusion (I/R), after they exhaust antioxidant reserves, they exert their harmful effect on cellular structures. The major significant reactive oxygen species (ROS) are the anion of superoxide (O2•-), the hydrogen peroxide (H2O2), and the hydroxyl radical (OH). The collective term reactive nitrogen species (RNS) mainly includes the radical of nitric oxide (NO), the peroxynitrite potent oxidant (ONOO), the radical nitrogen dioxide (NO2), and other nitrogen oxides. During ischemia, the tissue cells begin to suffer, when the oxygen delivery (DO2) to tissues decreases beyond the critical DO2 (cDO2) level, namely, when the metabolism becomes anaerobic. The cell suffering maximizes, when beta-oxidation of fatty acids is the last fuel that still feeds oxidative phosphorylation. Further drop of DO2 leads to severe ischemia with intracellular conversion of xanthine dehydrogenase to xanthine oxidase and increased concentration of xanthine and hypoxanthine. Upon reperfusion and abundant O2 reentry, free radical burst follows, with membrane destruction and massive cellular damage, mainly coming from the peroxidation of lipid bilayer arrangement. Suggested methods of I/R injury prophylaxis are the use of antioxidants, scavengers, and preconditioning techniques. The new approaches that seem to be promising focus on the progressive reentry of O2 to the thirsty for O2 ischemic tissues: initially in low concentrations of O2 to meet the low potentials of biochemical pathways to use O2 and thereafter in gradually increasing concentrations toward normal. Large, open, double blind, multicenter trials are still lacking.


I/R injury Adenosine triphosphate Oxidative stress Reactive oxygen species Reactive nitrogen species Xanthine oxidase Xanthine dehydrogenase 



adenosine triphosphate


constitutive NO synthase


oxygen delivery


glutathione reductase


glutathione reduced


glutathione disulfide


inducible NO synthase




metal-binding proteins




oxidized/reduced adenine dinucleotide


oxidized/reduced adenine dinucleotide phosphate


oxygen extraction ratio


reactive nitrogen species


reactive oxygen species


oxygen consumption


xanthine dehydrogenase


xanthine oxidase


xanthine oxidoreductase


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Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Emmanuel E. Douzinas
    • 1
  • Aikaterini Apeiranthitis
    • 2
  1. 1.3rd Department of Critical Care, Evgenidio HospitalAthens University School of MedicineAthensGreece
  2. 2.4th Department of Internal MedicineEvangelismos HospitalAthensGreece

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