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

      research-article
      a , * , b
      Redox Biology
      Elsevier
      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), Ischemia-reperfusion, Hypoxia-reoxygenation, Xanthine oxidase, NADPH oxidase, Uncoupled nitric oxide synthase, Mitochondria

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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.

          Graphical abstract

          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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          Most cited references497

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          Oxygen-derived free radicals in postischemic tissue injury.

          J M McCord (1985)
          It is now clear that oxygen-derived free radicals play an important part in several models of experimentally induced reperfusion injury. Although there are certainly multiple components to clinical ischemic and reperfusion injury, it appears likely that free-radical production may make a major contribution at certain stages in the progression of the injury. The primary source of superoxide in reperfused reoxygenated tissues appears to be the enzyme xanthine oxidase, released during ischemia by a calcium-triggered proteolytic attack on xanthine dehydrogenase. Reperfused tissues are protected in a variety of laboratory models by scavengers of superoxide radicals or hydroxyl radicals or by allopurinol or other inhibitors of xanthine oxidase. Dysfunction induced by free radicals may thus be a major component of ischemic diseases of the heart, bowel, liver, kidney, and brain.
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            Pathophysiology of ischaemia-reperfusion injury.

            Reperfusion of ischaemic tissues is often associated with microvascular dysfunction that is manifested as impaired endothelium-dependent dilation in arterioles, enhanced fluid filtration and leukocyte plugging in capillaries, and the trafficking of leukocytes and plasma protein extravasation in postcapillary venules. Activated endothelial cells in all segments of the microcirculation produce more oxygen radicals, but less nitric oxide, in the initial period following reperfusion. The resulting imbalance between superoxide and nitric oxide in endothelial cells leads to the production and release of inflammatory mediators (e.g. platelet-activating factor, tumour necrosis factor) and enhances the biosynthesis of adhesion molecules that mediate leukocyte-endothelial cell adhesion. Some of the known risk factors for cardiovascular disease (hypercholesterolaemia, hypertension, and diabetes) appear to exaggerate many of the microvascular alterations elicited by ischaemia and reperfusion (I/R). The inflammatory mediators released as a consequence of reperfusion also appear to activate endothelial cells in remote organs that are not exposed to the initial ischaemic insult. This distant response to I/R can result in leukocyte-dependent microvascular injury that is characteristic of the multiple organ dysfunction syndrome. Adaptational responses to I/R injury have been demonstrated that allow for protection of briefly ischaemic tissues against the harmful effects of subsequent, prolonged ischaemia, a phenomenon called ischaemic preconditioning. There are two temporally and mechanistically distinct types of protection afforded by this adaptational response, i.e. acute and delayed preconditioning. The factors (e.g. protein kinase C activation) that initiate the acute and delayed preconditioning responses appear to be similar; however the protective effects of acute preconditioning are protein synthesis-independent, while the effects of delayed preconditioning require protein synthesis. The published literature in this field of investigation suggests that there are several potential targets for therapeutic intervention against I/R-induced microvascular injury. Copyright 2000 John Wiley & Sons, Ltd.
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              The sites and topology of mitochondrial superoxide production.

              Mitochondrial superoxide production is an important source of reactive oxygen species in cells, and may cause or contribute to ageing and the diseases of ageing. Seven major sites of superoxide production in mammalian mitochondria are known and widely accepted. In descending order of maximum capacity they are the ubiquinone-binding sites in complex I (site IQ) and complex III (site IIIQo), glycerol 3-phosphate dehydrogenase, the flavin in complex I (site IF), the electron transferring flavoprotein:Q oxidoreductase (ETFQOR) of fatty acid beta-oxidation, and pyruvate and 2-oxoglutarate dehydrogenases. None of these sites is fully characterized and for some we only have sketchy information. The topology of the sites is important because it determines whether or not a site will produce superoxide in the mitochondrial matrix and be able to damage mitochondrial DNA. All sites produce superoxide in the matrix; site IIIQo and glycerol 3-phosphate dehydrogenase also produce superoxide to the intermembrane space. The relative contribution of each site to mitochondrial reactive oxygen species generation in the absence of electron transport inhibitors is unknown in isolated mitochondria, in cells or in vivo, and may vary considerably with species, tissue, substrate, energy demand and oxygen tension. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                08 October 2015
                December 2015
                08 October 2015
                : 6
                : 524-551
                Affiliations
                [a ]Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, United States
                [b ]Department of Physiological Sciences, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
                Author notes
                [* ]Corresponding author. Fax: +1 318 675 6005. dgrang@ 123456lsuhsc.edu
                Article
                S2213-2317(15)00110-X
                10.1016/j.redox.2015.08.020
                4625011
                26484802
                bec52497-20f7-440e-b308-c10c1dfe8d33
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 28 August 2015
                : 31 August 2015
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                Research Paper

                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),ischemia-reperfusion,hypoxia-reoxygenation,xanthine oxidase,nadph oxidase,uncoupled nitric oxide synthase,mitochondria
                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), ischemia-reperfusion, hypoxia-reoxygenation, xanthine oxidase, nadph oxidase, uncoupled nitric oxide synthase, mitochondria

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