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

  • Emmanuel E. Douzinas
  • Aikaterini Apeiranthitis
Chapter

Abstract

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.

Keywords

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

Abbreviations

ATP

adenosine triphosphate

cNOS

constitutive NO synthase

DO2

oxygen delivery

GR

glutathione reductase

GSH

glutathione reduced

GSSG

glutathione disulfide

iNOS

inducible NO synthase

LTF

lactoferrin

MBPs

metal-binding proteins

MPO

myeloperoxidase

NAD+/NADH

oxidized/reduced adenine dinucleotide

NADP+/NADPH

oxidized/reduced adenine dinucleotide phosphate

O2ER

oxygen extraction ratio

RNS

reactive nitrogen species

ROS

reactive oxygen species

VO2

oxygen consumption

XDH

xanthine dehydrogenase

XO

xanthine oxidase

XOR

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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