Elsevier

Redox Biology

Volume 6, December 2015, Pages 524-551
Redox Biology

Research paper
Reperfusion injury and reactive oxygen species: The evolution of a concept

https://doi.org/10.1016/j.redox.2015.08.020Get rights and content
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open access

Highlights

  • Reperfusion injury is implicated in a variety of human diseases and disorders.

  • Evidence implicating ROS in reperfusion injury continues to grow.

  • Several enzymes are candidate sources of ROS in post-ischemic tissue.

  • Inter-enzymatic ROS-dependent signaling enhances the oxidative stress caused by I/R.

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Abstract

Reperfusion injury, the paradoxical tissue response that is manifested by blood flow-deprived and oxygen-starved organs following the restoration of blood flow and tissue oxygenation, has been a focus of basic and clinical research for over 4-decades. While a variety of molecular mechanisms have been proposed to explain this phenomenon, excess production of reactive oxygen species (ROS) continues to receive much attention as a critical factor in the genesis of reperfusion injury. As a consequence, considerable effort has been devoted to identifying the dominant cellular and enzymatic sources of excess ROS production following ischemia-reperfusion (I/R). Of the potential ROS sources described to date, xanthine oxidase, NADPH oxidase (Nox), mitochondria, and uncoupled nitric oxide synthase have gained a status as the most likely contributors to reperfusion-induced oxidative stress and represent priority targets for therapeutic intervention against reperfusion-induced organ dysfunction and tissue damage. Although all four enzymatic sources are present in most tissues and are likely to play some role in reperfusion injury, priority and emphasis has been given to specific ROS sources that are enriched in certain tissues, such as xanthine oxidase in the gastrointestinal tract and mitochondria in the metabolically active heart and brain. The possibility that multiple ROS sources contribute to reperfusion injury in most tissues is supported by evidence demonstrating that redox-signaling enables ROS produced by one enzymatic source (e.g., Nox) to activate and enhance ROS production by a second source (e.g., mitochondria). This review provides a synopsis of the evidence implicating ROS in reperfusion injury, the clinical implications of this phenomenon, and summarizes current understanding of the four most frequently invoked enzymatic sources of ROS production in post-ischemic tissue.

Abbreviations

A/R
anoxia-reoxygenation
AP-1
activator protein-1
BH4
tetrahydrobiopterin
BM
bone marrow
CoQ
coenzyme Q
CuZn SOD
copper–zinc superoxide dismutase
ψ
membrane potential
DCF
dichlorofluorescein
DHE
dihydroethidine
DHFR
dihydrofolate reductase
DHR
dihyrdrorhodamine
DPI
diphenyliodonium
Duox
dual oxidase
EC
endothelial cell
EC-SOD
extracellular superoxide dismutase
ESR
electron spin resonance
ETC
electron transport chain
FAD
flavin adenine dinucleotide
FADH2
reduced FAD
GAG
glycosaminoglycans
α-GPD
α-glycerophosphate dehydrogenase
GPx
glutathione peroxidase
GTPCH
guanosine triphosphate cyclohydrolase I
H2O2
hydrogen peroxide
H/R
hypoxia-reoxygenation
HIF-1α
hypoxia inhibitory factor-1α
I/R
ischemia-reperfusion
IMAC
inner membrane anion channel
ICAM-1
intercellular adhesion molecule-1
IFN-γ
interferon-γ
IL-1β
interleukin-1beta
IL-6
interleukin-6
α-KDH
α-ketoglutarate dehydrogenase
LTB4
leukotriene B4
MAO
monoamine oxidase
MnSOD
manganese superoxide dismutase
MPTP
mitochondrial permeability transition pore
mtROS
mitochondrial reactive oxygen species
NAD+
Nicotinamide adenine dinucleotide (oxidized)
NADH
Nicotinamide adenine dinucleotide (reduced)
NADPH
Nicotinamide adenine dinucleotide phosphate
NFkB
nuclear factor kappa-B
NNT
NADP-transhydrogenase
Nox
NADPH oxidase
NO
nitric oxide
NO2-
nitrite ion
NOS
nitric oxide synthase
eNOS
endothelial nitric oxide synthase
iNOS
inducible nitric oxide synthase
mtNOS
mitochondrial nitric oxide synthase
nNOS
neuronal nitric oxide synthase
O2
molecular oxygen
O2·-
superoxide anion
PDH
pyruvate dehydrogenase
PKC
protein kinase C
PR-39
synthetic peptide inhibitor of Nox
Prx
peroxiredoxin
PAF
platelet activating factor
PEG-
polyethylene glycol conjugated
RBC
red blood cell
RET
reverse electron transport
RIRR
ROS-induced ROS release
ROS
reactive oxygen species
SOD
superoxide dismutase
TCA
tricarboxyl acid
TNF-α
tumor necrosis factor-α
Trx
thioredoxin
UCP
uncoupling protein
XDH
xanthine dehydrogenase
XO
xanthine oxidase
XOR
xanthine oxidoreductase (XD+XO)

Keywords

Ischemia-reperfusion
Hypoxia-reoxygenation
Xanthine oxidase
NADPH oxidase
Uncoupled nitric oxide synthase
Mitochondria

Cited by (0)

Supported by a Grant from the National Heart Lung and Blood Institute (HL26441) and the KACST of Saudi Arabia (11-MED1672-20).