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NMR I 90-129Ga. NAME OF PERFORMING ORGANIZATION 6b. OFFICE SYMBOL 7a. NAME OF MONITORING ORGANIZATIONNaval Medical Research (if applicable) Naval Medical CommandInstitutei6c.* AgDDRESS (City, State, and ZIP Code) 7b . ADDRESS (City, State, and ZIP Code)t901 Wi sconsin Avenue Department of the NavyBethesda, MD 20889-5055 Washington, DC 20372-5120So. NAME OF FUNDING /SPONSORING Sb . OFFICE SYMIBOL 9. PROCUREMENT INSTRUMENT IDENTIFICATION NUMBERORGANIZATION Naval Medical (ifapplicable)Research &Development CommanSc . ADDRESS (City, State, and ZIP Code) 10. SOURCE OF FUNDING NUMBERS8901 Wis cons in Avenue POGRM PROJECT ITASK WORK UNITBethesda, MD 20889-50441 ELEMENT NO . NO . INO. CCESSION N1l153N R041 01.O001 11005N2 01

1.TITLE (Include Security Classification)Background review and curent concepts of reperfusion injury12. PERSONAL. AUTHOR(S) Ha IIenbeck JM Dutka AJ13a. TYPE OF REPORT 113b . TIME COVERED I14. DATE OF REPORT (Yer, Month 0Da) uS. PAGE COUNT

'oIurnal article FROM TO I1990 j 10)16 . SUPPLEMENTARY NOTATIONReprinted from: -Archives of Neurology 1990 November, Vol.47 No.11 pp. 124#5-54

17. COSATI CODES 16. SUBJECT TERMS (C&ntnue on reverse Nf neceuaiy and ident b lck number)FIELD 1GROUP $S-GROUP Stroke, cerebral ischemia, free radicals, white cells, reperfusion injur

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Reprinted from the Archives of eurologyNovember 1990, Volume 47Neurological Review Copyrigh e M

Background Reviewand Current Concepts of Reperfusion InjuryJohn M. Hallenbeck, MD, Andrew J. utka, MD

0 We define the concept of reperfusion blood and the damaged tissue can lead that the lesions were operation relatedinjury, and we present abackground chro- to further tissue injury. This theoret- and represented contracture due tonology of experimental work supporting ical construct implies that unmodified calcium loading and myocardial cellu-and questioning this concept. We identify blood is not an ideal perfusate for re- lar edema in the distribution of widelyseveral new influences, such as current flow to tissue subjected to prior is- patent arterial grafts. They furtherclinical interest in thrombolytic therapy for chemia. Its reintroduction can actually concluded that "prevention of intraop-acute ischemia of heart and brain and the contribute to parenchymal cell loss as erative myocardial injury must alsogrowing recognition of endothelium as a an unwanted side effect of its more fa- focus on characteristics of the phase ofregulator of homeostasis. We propose that miliar capacity to salvage reversibly myocardial reperfusion." Studies bythese influences will encourage a eexam- damaged cells. This paradoxically Greene and Weisfeldt and by Shineination of reperfusion injury as a factor in harmful aspect of blood flow return and Douglas8 demonstrated that mea-the ultimate outcome of tissue exposed to has been termed reperfusion injury sures instituted after the terminationreversible ischemia.We briefly discuss the (Fig 1, bottom), and the process has of ischemia, which attenuated the risemajor mechanisms presently implicated in potential relevance to clinical medi- in myocardial cytosolic calcium, led toreperfusion injury-loss of calcium ho- cine. Although reperfusion per se is a reduction of tissue injury. Subse-meostasis, free radical generation, leuko- essential to functional recovery and quently, other workers have impli-cyte-medlated injury, and acute hypercho- reduces the volume of tissue infarcted, cated cell swelling,9 white blood celllesterolemia. a further reduction in tissue loss might plugging of vessels,'" and free radical(Arch Neurol. 1990;47:1245-1254) be achieved by measures that counter- damage" in reperfusion injury of the

act reperfusion injury. The present re- heart.view addresses the major mechanisms Ames an d coworkers' focused at-During focal ischemia, the extent of currently implicated in reperfusion in- tention on the contribution of reperfu-parenchymal tissue damage re- jury as observed in brain, heart, and sion impairment to neural injury.lates closely to two factors: the level of other organs. The role of excitotoxins Based on a disproportionately longblood flow during the ischemic interval is not emphasized in this review. survival of retinal ganglion cells ex-and the duration of ishemia (Fig 1,ACKGROUND posed to anoxia in culture (in whichtop).-, oxygen could diffuse directly to theOn return of blood flow, there is a Reperfusion injury occurs in a vari- cells when reintroduced rather thanresumption of the principal functions ety of tissues, bu t much of the work on requiring an intact tissue perfusion) asof tissue perfusion: oxygen delivery, these phenomena has been done in compared with the rapidity with whichprovision of substrates for metabo- heart and brain. Concepts of reperfu- ischemia in vivo leads to irreversiblelism, and clearance of metabolic sion injury tend to emphasize similar- brain cell damage," they postulatedwastes. The restored perfusion coun- ities between mechanisms of cell death that recirculation of ischemic brainteracts the ischemic injury process and in various tissues rather than proper- could become compromised and ac-serves to return at least some of the ties unique to a given tissue. Concern count for the differences in neuronalreversibly injured tissue to a func- about myocardial reperfusion was ex- vulnerability observed under the twotional state. However, there is a devel- pressed by Jennings et alin 1960, conditions. This impairment of mi-oping consensus that return of blood when they suggested that reperfusion crovascular reperfusion was attrib-flow in the postischemic period has a may accelerate the development of ne- uted primarily to two phenomena. Thedark side.' Interactions between crosis in irreversibly injured myo- first was narrowing of the capillarycytes. They observed an ultrastruc- lumen due to perivascular swelling andAccepted fo r publication April 30 , 1990. tural appearance of "explosive swell- formation of endothelial blebs, and theFrom the Neurology Department, National Na- ing," which included architectural second was increased blood viscosity.val Medical Center, Bethesda, Md . disruption, contraction bands, and in- Fluid shifts into cells, with their sodi-The opinions and assertions contained hereinare the private ones of the authors and are not to tramitochondrial calcium phosphate um-potassium adenosine triphos-be construed as official or reflecting the views of granules. In 1977, Bulkley and phatase pumps shut down by energythe Navy Department or the Naval Service at Hutchins' reported the paradox of failure, were thought to underlie both

largep myocardial necrosis after successful the capillary narrowing an d the mi-eprint requests to Neurology Department,National Naval Medical Center, 8901 Wisconsin revascularization by coronary artery crovascular hemoconcentration withAve, Bethesda, MD 20814-5011 (DrHallenbeckl. bypass graft surgery and suggested increased blood viscosity. This sameArch Neurol-Vol 47, November 1990 Reperfusion Injury-Hallenbeck &Dutka 1245

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' _ _ _Ischmia flow deficits by raising blood pressure ther interest in neuronal self-destruc-/,0 had no effect on mortality. 0 Some au - tion has been fostered by the ob-

SoReversible Infarction thors developed the view that no re- servation in a number of models thatDeficit flow wa s a consequence of ischemic a process of delayed neuronal deathEo10 brain injury rather than a proximal can progress for days aftercause of it.2' brief ischemia ' .2" and may involve

O The concept of a multifocal impair- excitotoxins, such as glutamate and- Duration of Ischemia ment of reflow manifesting immedi- aspartate acting via the N-methyl-

Reperfusion ately after ischemia and decreasing D-aspartatel receptor to initiate ano with time was modified and extended accumulation of calcium ion in the cy-by consideration of "autodestruction" tosol via agonist-operated channels.in models of spinal cord trauma and Because the transition of glutamatereperfusion problems encountered from neurotransmitter to neurotoxinduring autotransplantation of organs may depend on elimination of the volt-preserved by ex vivo perfusion. 2 Re- age-dependent Mg2 block of theHours 0 Days turning blood flow was viewed as hav- N-methyl-D-aspartate receptor chan-ing two dichotomous effects: (1) a well- nel by local interference with glucoseFig 1.-Top, Interaction between the level of established restorative effect and (2) a and oxygen delivery as shown in cul-residual blood flow and the duration of is-

chemia in an ischemic injury zone that deter- postulated capacity to undergo a mul- tured cerebellar neurons,1progressivemines the amount and degree of tissue dam- tifactoral interaction with damage tis- microcirculatory flow shutdown couldage. During ischemia, lower residual flows are sue that could progressively shut down act in concert with excitotoxins to pro-tolerated for shorter periods than higher resid- microcirculatory flows and contribute duce delayed neuronal death. That is,ual flows. LCBF indicates local cerebral blood to further neuronal damage. Levy et these two potential mechanisms forflow. Bottom, The upper curve represents a a12' measured blood flow and metabo- delayed neuronal death ma y not betheoretically optimal reperfusion devoid of any lism in gerbils subjected to unilateral mutually exclusive.injurious influence on the previously ischemic carotid occlusion, and they noted an In recent years, several new devel-tissue. The return of oxygen and substrates for immediate return of perfusion to the opments have returned attention tometabolism and the clearance of metabolic bmmi o of perfusion toh ooments reund aention towastes promote a rapid recovery of cellular brain on release of the occlusion, fol- blood elements, blood vessels, andfunction that reaches the maximum possible lowed in 10 to 30 minutes by a decline blood flow in ischemically damagedlevel and is sustained. In contrast, the lower in flow for at least 4 hours with a coin- tissue. Th e demonstration that coro-curve denotes reperfusion injury with conse- cident rise in the cerebral metabolic nary thrombi were obstructing vesselsquent retardation and attenuation of cellular rate that disrupted the normal flow- that supplied ischemic myocardium inrecovery. Furthermore, the maximal level of metabolism couple. They introduced the great majority of patients studiedrecovery is not sustained, but yields instead to the term delayed postischemic hypo- angiographically during the first hoursprogressive secondary damage. perfusion to describe this phenome- of acute transmural myocardial in-

non. Pulsinelli and colleagues" then farction" and experiments that indi-documented this phenomenon in the cated that myocardium can be salvagedlaboratory adduced experimental sup- four-vessel occlusion model that they by reperfusion led to efforts to lyse theport for these concepts in a series of had devised in rats. offending thrombi and reopen supplyarticles." In addition, others described In 1981, Siesjo2' published his specu- vessels."-" Several trials of thromboly-the topography of "no reflow,"' 5 and lative synthesis, which culminated sis in cerebrovascular disease are alsopublished provocative studies have with the insight that elevation of the under way." These initiatives bring todemonstrated the resumption of func- cytosolic calcium level may be a pivotal the fore the problem of reperfusion in-tion in cortical neurons after total is- factor that leads to cell death in such jury in a clinical setting.chemia for periods of 30 minutes to diverse conditions as ischemia, hypo- Another force that impels consider-1hour if measures were taken to over- glycemia, and status epilepticus. Th e ation of blood elements, blood vessels,come reperfusion impairment."'-" disruption of calcium homeostasis was and blood flow during and after is-Th e theory that vessel shutdown attributed to energy failure in ischemia derives from work in endothe-during ischemia could occur at a time chemia and hypoglycemia and to over- lial cell tissue culture. Results of thiswhen nerve cells were still potentially loading of calcium transport and se- work implicate endothelium as a regu-viable collided with a deeply ingrained questration mechanisms in status ep - lator of hemostasis. Endothelium istenet that neurons are uniquely sensi- ilepticus. Among many other studies, a not simply a passive, nonthrombogenictive to hypoxia and ischemia. Th e no- provocative set of results reported by surface that separates blood fromreflow theory was attacked on the Schanne et a 2 in 1979 was cited in tissue. 5", ' It is endowed with ultra-grounds that the observed distribution support of this hypothesis. Schanne structural specializations, such as pro-of microvessel occlusion did not corre- and associates" had observed that the jections, caveolae, and microdomains.spond to the distribution of neurons expression of toxicity of a variety of Indeed, endothelial projections or mi-that exhibit selective vulnerability membrane toxins, added to cultured crovilli have been observed to prolif-and that compression of the vascular hepatocytes, depended on the presence erate after ischemia, indicating mem-lumen by swollen perivascular astro- of calcium in the culture medium. That brane activation and reducing to somecytes and swollen endothelial cells is, calcium was required for the death degree the vascular lumen." There is awith bleb formation was seldom ob- of cells in that system. Th e clear and carpet of molecules on the luminalserved in histopathological material."' compelling reasoning in the communi- surface of endothelium called the gly-Several experiments in gerbils re- cation of Siesjo"l focused attention on cocalyx that has not been fully charac-vealed that extensive postischemic mechanisms for continuing cell dam- terized. It is a well-hydrated, complex,neuronal damage could occur with a age that were intrinsic to the neuron cross-linked polymer that contains fi-patent microvascular bed' 9 and that and tended not to emphasize events at bronectin, a form of collagen, gly-elimination of focal microcirculatory the blood-endothelial interface. Fur- cosaminoglycans, and probably fibrin1246 Arch Neurol-Vol 47 , November 1990 Reperfusion Injury-Hallenbeck &Dutka


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mines the amount of vasocon- calcium concentration recovers in is currently undergoing intensivestriction.46With endothelial cell dam- models of traumatic and ischemic neu- evaluation.?'8age, the unopposed mediators of vessel ronal injury. This delayed neuronal Free Radicalscontraction lead to enhanced vasocon- damage has been attributed to a cal-striction and, potentially, a reduction cium paradoxlike reaction that occurs The following is based on threeof blood flow to critical levels. In addi- in injured nervous system tissues on reviews"-92 A free radical is a moleculetion to its influence on vasomotor tone, restoration of extracellular calcium or molecular fragment that containsendothelium-derived relaxing factor levels toward normal. one or more unpaired electrons in itshas also been shown to inhibit adhe- Calcium homeostasis can also be outer orbital and is, in effect, an opension of platelets to endothelium." disrupted by ischemia (Fig 2)4215-114 due bond. The presence of an unpaired sin-A 21-residue vasoconstrictor pep- to interference with sodium-potas- gle electron in the outer orbital of atide has been isolated from endothe- sium adenosine triphosphatase func- free radical is conventionally. repre-]ium, sequenced, and designated tion, which depolarizes cell mem- sented by a superscript dot (RV). Mo-endothelin.'8 It is the most potent branes and permits intracellular so- lecular oxygen is a biradical with anmammalian vasoconstrictor known to dium accumulation. This can cause unpaired electron in each of its twodate. opening of voltage-dependent calcium outer orbitals, both spinning in the

Thus, the intricate and interwoven channels and reverse the sodium-cal- same direction (ie, parallel), which re-mechanisms that are being elucidated cium antiport system, such that cal- duces the reactivity of this biradicalin endothelial cell tissue culture con- cium enters the cell as sodium is ex- because its divalent reduction by di-fer on the blood-endothelial interface truded. The major emphasis in the rect addition of a pair of electrons isthe capacity for a variety of cell-dam- neuroscience literature is currently on restricted. Most of the electron donorsaging reactions during ischemia and the activation of N-methyl-D-aspar- available to oxygen will have electronsreperfusion. Such studies will encour- tate receptors in response to gluta- with antiparallel spins that occupy theage a reexamination of local blood and mate and other excitotoxins that are valence orbitals, as this is a lower en-vessel wall interactions during the released during and after ischemia ergy condition. For molecular oxygenearly return of blood flow to previously with a consequent rise of cytosolic cal- to remove two electrons concomitantlyischemic tissue. cium. Calcium-activated nonspecific from a nonradical molecule that has

MAJOR POSTULATED MEDIATORS OF cation channels may also be opened. In the normal outer orbital configurationREPERFUSION INJURY addition, sequestering mechanisms of pairs of electrons spinning in oppo-Calcium within cells become impaired, and cal- site directions, an electron spin inver-cium moves from the endoplasmic re- sion must first occur during the asso-Calcium has been implicated in ticulum into the cytosol. The cellular ciation of oxygen with the reducingreperfusion injury under several cir- disturbances associated with elevation agent.cumstances. Zimmerman and Huls- of cytosolic calcium include activation Because the spin inversion process ismann19 described a "calcium paradox" of proteases and phospholipases slow (=10- seconds) compared within which hearts perfused with calcium- (which can lead to free radical gener- the lifetime of collisional complexesfree media for a brief period developed ation), membrane damage, and forma- (=10-" seconds), oxygen in its groundsarcolemmal damage, such that rein- tion of arachidonic acid metabolites. state is a relatively weak oxidant. Thetroduction of calcium caused massive Also, mitochondria can become over- restriction in the oxidizing capabilitiesintracellular influx of this ion with loaded with calcium, which impairs of molecular oxygen is removed whenconsequent tissue disruption, enzyme production of adenosine triphosphate. it acquires one electron at a time be-release, development of contracture, Reperfusion can cause an acute accel- cause under these circumstances, spinand marked reductions of high-energy eration of calcium influx into cells by inversion need not occur. This is thephosphate stores. This circumstance is injuring cell membranes with a conse- univalent pathway of oxygen reduc-peculiar to situations in which a heart quent increased membrane perme- tion (Fig 3), and sequential addition ofis temporarily exposed to an artificial ability .4 one electron after another to molecu-perfusate that is deficient in calcium. The exact role of cytosolic calcium lar oxygen produces first the superox-Young' has extended this concept to accumulation in the evolution of neu- ide anion radical (0.7), then hydrogentraumatically or ischemically injured ronal and myocardial injury after is- peroxide (H20), and then the hydroxylbrain. Extracellular calcium in these chemia remains to be elucidated, but radical (OH ),followed by water as theinjured areas has been observed to fall there is considerable evidence that is- final product.from concentrations greater than chemia and reperfusion are associated The reactivity of molecular oxygen1 mmol to less than 0.01 mmol within with a severe disruption of calcium can be increased by reactions that in-seconds to minutes as this cation pours homeostasis. Recent reports demon- vert the spin of one of the electrons ininto those critically injured cells that strate, however, that considerable its two outer orbitals. The UV spectrahave lost their capacity to maintain functional impairment can occur in of such oxygen molecules contain sin-calcium homeostasis. The calcium con- the absence of calcium entry into cells 5 glet lines that indicate the presence ofcentration in the extracellular space and that the concentration of intracel- electrons with antiparallel spins in thethen rises during a period of hours due lular calcium can rise considerably outer orbitals. These molecules,to calcium diffusion from surrounding without leading to permanent dam- termed singlet oxygen, are highly re-tissues. The surviving neurons in the age. Moreover, the results of calcium active because of the removal of quan-lesion site, which initially maintained channel blocker treatment trials have tum mechanical spin restriction sotheir calcium homeostasis, may there- been mixed in a variety of models."" that they can undergo divalent reduc-fore be exposed to the same stimuli The contribution of intracellular cal- tion. There are two types of singlet ox -that produce the calcium paradox in cium flooding to cell death during is- ygen, a short-lived sigma singlet oxy-cardiac tissues. Delayed acceleration chemia and reperfusion should be gen ('g+) in which the electrons oc -of tissue damage has been observed to viewed not as established fact but cupy separate orbitals and a a longer-occur at about the time extracellular rather as an attractive hypothesis that lived delta singlet oxygen ('AgO2 ) in1248 Arch Neurol-Vol 47, November 1990 Reperfusion Iniury-Hallenbeck &Dutka


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which the two electrons occupy thesame orbital and have opposite spin Agonist-Dependentdirections. Singlet oxygen can beformed by light, acting on molecular Ca'oxygen in the presence of a photosen-sitizer. Other postulated reactions in-volve dismutation of the superoxide ASPanion radical and the oxidation of ha- (Ca ) 10- Mlides by hydrogen peroxide, a reactioncatalyzed by myeloperoxidase, as oc- K+curs during the antimicrobial activity AT P Na' , Ca-of inflammatory cells. Delta singletoxygen does not fulfill the definition of (Ca++), 10-' M Voltage-Dependenta free radical but can rapidly oxidize AT Pmany molecules, including polyunsat-urated fatty acids in cell membranes. NaAlthough a number of enzyme sys-tems appear to be capable of catalyzing Cc P + AD P Cathe univalent reduction of molecularoxygen to the superoxide anion radical, ERinterest in the reperfusion injury fieldhas been focused primarily on twomajor systems, the xanthine oxidasesystem"' and the nicotinamide-adenine Fig 2.-A 10 000-fold concentration difference between intracellular and extracellular calcium anddinucleotide phosphate with the re- the internal negativity of the cell create a steep electrochemical gradient for calcium entry, whichduced form (NADP[H]), NAD[H] oxi- is normally tightly regulated by voltage- and agonist-dependent channels. Calcium that does enterdase system (Fig 4).4 Due to the low can be extruded by means of a number of adenosine triphosphate (ATP)-dependent processes.levels of xanthine oxidase in brain, the including a calcium-activated ATPase and an electrogenic (3:1) Na* ICa 2* antiport system drivenrelevance of the xanthine oxidase sys- by the sodium gradient that is itself maintained by the sodium-potassium ATPase. Excess intra-tern to reperfusion injury in that organ cellular calcium can be sequestered in endoplasmic reticulum (ER) by an ATP-dependent processremains an open question. Several re- and can also associate with a variety of calcium-binding proteins (CaBP). Mitochondria possesscent articles suggest that xanthine ox- a high-capacity uniport mechanism for calcium uptake, which relies on the potential across theinner mitochondrial membrane to translocate electrophoretically calcium internally. Intramitochon-idase is formed in ischemic brain and drial calcium levels can normally be regulated by an antiport system that exchanges 2 Na' formay generate free radicals and con- I Ca 2* . As the capacity of this efflux pathway is less than 10% of the influx pathway, it can betribute to neuronal injury during overwhelmed under conditions of markedly elevated levels of free cytosolic calcium. reringpostischemic reperfusion.'5 ischemia, ATP production becomes impaired, and ATP-dependent processes fail. Membrane ,ra-Another potentially important dients for sodium and potassium cannot be maintained, and the membrane depolarizes ol..ningsource of the superoxide anion radical voltage-dependent calcium channels. Excitatory neurotransmitters, glutamate (GLUT), andduring ischemia is a "univalent leak" aspartate (ASP), are released and act via the N-methyl-D-aspartate receptor to increase furtherof this radical species from the mito- calcium influx. As intracellular sodium rises, the Na / Ca 2 antiport system becomes reversed andtranslocates calcium into the cell. Sequestration mechanisms become overwhelmed or stalled bychondrial electron transport system, lack of ATP, and mitochondria become flooded with calcium (modified from Siesjo' 32).The next step in the univalent re-duction of oxygen involves conversionof the superoxide anion radical to peroxidase, brain trauma with acute hyper-H20 2.This can occur spontaneously but 2 GSH + H202 - GSSG + 2HO tension Such perturbation activatesis greatly accelerated by the enzyme, and catalase, phospholipases in the vessel wall, lead-superoxide dismutase, in the following ing to a release of free arachidonate.reaction: 2H,0 2 -0 0 + 2H,O. The released free arachidonate causes

07- + O + 2H- - H20, + 0, If these protective reactions should accelerated metabolism via cyclooxy-become insufficient to contain free rad- genase, producing PGG2 (a cyclic en-The OH', the next step in the univa- icals as they are formed, 0"2 and H202 doperoxide) that is then converted tolent 02 reduction pathway, can be can diffuse across cell membranes to PGH2 (a cyclic endoperoxide) by theformed via two reactions: (1) The the extracellular space in which an- hydroperoxidase reaction. This step"Fenton" reaction, tioxidant defense mechanisms are rel- generates superoxide as a by-productFe ' + H202 -. Fe ' * + OH + OH - atively sparse. In the presence of trace that escapes to the extracellular space

and (2) the iron-catalyzed "Haber- concentrations of transition metal via the anion channel. Subsequent re-Weiss" reaction, ions, OH * is formed that can initiate actions can form H202 and OH', caus-free radical chain reactions in cell ing membrane damage to cells of the0- + H2O: -p Fe'O, + OH' + OH. membranes, causing peroxidation of vessel wall. As with disruption of cal-Due to the reactivity of OH', no en- polyunsaturated fatty acids. Such per- cium homeostasis, the importance ofzyme systems exist that involve it as a oxidation severely damages the cell oxygen-derived free radical formationsubstrate. Instead, all efforts of the cell membrane and causes loss of mem- in reperfusion injury is a researchare directed at avoiding its formation. brane fluidity and collapse of trans- question under active investigation.The superoxide anion radical is scav- membrane ionic gradients. Leukocytesenged by superoxide dismutase, so that A novel pathway for superoxide gen-it is not available for the Haber-Weiss eration in response to vessel injury has The scope and diversity of possiblereaction and H,0 2 can be removed by been elucidated and experimentally leukocyte reactions in a zone of tissuereactions catalyzed by glutathione supported principally in models of injury that may involve rheologic ef-Arch Neurol-Vol 47, November 1990 Reperfusion Injury-Hallenbeck & Dutka 1249


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e-a e+ 2H* e +H' e- +H02 -. 0 i H202 "v-- OH H20 Hexose MyeloperoxidasH20 Y. :.,Monophosphate

Superoxide Hydrogen Hydroxyl ShuntPeroxide Radical NADP-ADPH 02xCA- + H202Fig 3.-The univalent pathway of oxygen re- NADPduction (where e- is electron and H+, hydrogenion).

fects, toxic oxygen products, granule ATP HOCIconstituents, and phospholipase prod- 41ucts qualify these cells for a central ADProle in many of the postulated modes of 4'reperfusion injury."," As large, stiff,viscoelastic cells that adhere to endo- ,thelium, activated leukocytes can ob- Adenosine Xanthine Dehydrogenasestruct individual capillaries in an is- 4 Cal+ I Calpainchemic injury zone and increase diffu- Inosinesion distances for oxygen within the 4' Xanthine Oxidasemicroenvironment of individual nerve Hypoxanthine 0 + H,02+ Uratecells.'" Leukocytes can also generate avariety of reduced oxygen products Fig 4. -Two free radical generating systems are depicted. The nicotinamide adenine dinucleotidethat are capable of initiating lipid phosphate (NADPH) oxidase system in leukocyte membranes (neutrophils, eosinophils, mono-peroxidation in cell membranes and cytes, and macrophages) has a pyridine nucleotide binding site on the cytoplasmic surface anddamaging key intracellular compo- an 02 forming oxidase component in the lipid bilayer so that 02, is generated on the external sur-nents." In addition, neutrophil gran- face of the plasma membrane. Subsequent reactions produce hydrogen peroxide (H20 2) that cancombine with Cl- in a reaction catalyzed by myeloperoxidase to produce hypochlorous acidules contain a number of constituents (HOCI). The xanthine oxidase system is concentrated in endothelium. During ischemia, xanthinecapable of mediating tissue injury.98' 1 dehydrogenase is converted by a calcium-activated protease (possibly calpain) to xanthine ox-It was initially assumed that extracel- idase, an enzyme that produces 02"-, H202 , and uric acid from hypoxanthine and molecular oxy-lular release of cytotoxic products oc- gen. The hypoxanthine substrate that is supplied by the ischemia-induced degradation of adeninecurred only after the death of neutro- nucleotides and molecular oxygen, which is not shown in the diagram, becomes available duringphils in inflammatory lesions, bu t it is reperfusion. AT P indicates adenosine triphosphate; ADP, adenosine diphosphate; and AMP, ad-now recognized that viable leukocytes enosine monophosphate.that have been activated can releasesuch products. Also, activation ofphospholipases in leukocytes can ini- Relative to the red blood cell, the rouleau of packed red blood cells, tendstiate a cascade of reactions that pro- leukocyte has roughly double the vol- to occlude each involved capillary.duce such vasuactive substances as ume, a coefficient of viscosity that is Measured blood flow can progressivelyleukotrienes and PAF.""2 Vasocon- 2100 times greater, and an entry time decrease during ischemia and reperfu-striction, increased permeability, and into capillaries that is three orders of sion, particularly in the endocardium,increased leukocyte adherence are magnitude greater." ,1" Activated leu- but a considrable percentage of indi-among the vascular effects of these kocytes undergo receptor-mediated vidual capillaries can become ob-mediators. adhesion to intact endothelium by structed without increasing total rest-There are a variety of endogenous means of the CD11/CD18 receptor ing vascular resistance or decreasinginhibitors and regulators of leukocyte- complex on leukocytes"2 and corre- average flow because of the parallelmediated vascular injury. These in- sponding receptors on endothelial cells arrangement of channels. Obstructionclude chemotactic factor inhibitor,03 that are of two described types: (1) the of several adjacent capillaries may re-neutrophil-derived proteases,'" and endothelial-leukocyte adhesion mol- sult in underperfusion of individualneutrophil-generated oxidants'0 that ecule"3 and intercellular adhesion mol- cells, however. In an area neighboringinactivate chemotaxins, and plasma ecule-l." Expression of receptors on the blocked capillaries, mean diffusionfactors that inactivate PAF 10 and neu- leukocytes is stimulated by N-formyl- distances for oxygen, normally abouttral proteases." Scavengers ' 9 and methionyl-leucyl-phenylalanine and 1.5 cell diameters, can be increased,antioxidant enzymes,'"'1 which clear PAF. Receptor expression on endothe- and the local partial pressure of oxy-neutrophil-generated oxidants, also lial cells is stimulated by IL-1. Li- gen can approach zero. A process ofparticipate. There is an apparent re- popolysaccharide, TNF, and leuko- this sort that causes scattered occlu-quirement for neutrophil adhesion be- triene B4 stimulate receptor expres- sions in the capillary network couldfore endothelial cell damage by acti- sion on both leukocytes and endo- expose individual cells to a hypoxicvated neutrophils can proceed." Adhe- thelial cells.' 4 microenvironment but would largelysion under these circumstances seems Evidence has been adduced by En- escape detection by the current tech-to create an environment that is pro- gler et al'""' that leukocytes can ad- niques for measuring blood flow. Gran-tected from endogenous inhibitors and here to endothelium within an is- ulocytes, labeled with indium 111, havethus permits leukocyte-mediated vas- chemic zone of myocardium during been observed to accumulate as earlycular injury to progress unhindered, both the ischemic and the early reper- as 1 hour after a 60-minute period ofThis apparent requirement supplies a fusion periods and block more than brain ischemia in an incremental airrationale for therapy directed at in- half of the available capillaries. On e embolism model in the dog,"' and thehibiting leukocyte adhesion. adherent leukocyte, trailed by a degree of accumulation has shown an1250 Arch Neurol-Vol 47 , November 1990 Reperfusion Injury -Hallenbeck &Dutka


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inverse relationship with local blood ules, are long lived, react repeatedly, neutrophils can create an environmentflow and evoked response recovery, and can select targets, all of which in which elastase, collagenase, and ge-Nentrophils and macrophages un- would seem advantageous. Of more latinase are able to exert destructivedergo a respiratory burst in which ox- than 20 enzymes in neutrophil gran- effects more efficiently and with greaterygen consumption increases twofold to ules, three have the greatest potential specificity than could be achieved by ox-20-fold and glucose metabolism via to mediate tissue destruction. One is a idants alone. Although this model isthe hexose monophosphate shunt serine proteinase, elastase. Th e other very attractive, and cell damage by ex-increases. 4 Greater than 90% of the two are metalloproteinases, collage- tracted granule constituents has beenoxygen consumed during this respira- nase and gelatinasc. Despite the de - demonstrated in a number of models intory burst can be accounted for by 0-, structive potential of proteinases, neu- vitro (as summarized by Harlan"), thesecretion. Tye enzyme system respon- trophil oxidants remain the focus of role of these enzymes in reperfusion in-sible for O-, generation has been iden- most of the current literature as final jury has not been directly studied.tified as a membrane-associated nico- mediators of tissue damage for three Leukocyte accumulation during is-tinamide-adenine dinucleotide phos- reasons. First, there are powerful chemia and reperfusion has been dem-phate (NADP[H], NAD[H] oxidase plasma antiproteinases in vivo that onstrated in a variety of organs, and(Fig 4). rapidly and irreversibly inhibit the direct and indirect evidence has beenRelease of granule constituents serine proteinases. Second, metallo- adduced by participation of leukocytesfrom leukocytes could potentially ex- proteinases are synthesized in latent, in reperfusion injury through rheo-tend tissue damage in an ischemic in- inactive forms, and physiologically logic effects, toxic oxygen products,jury zone. Weiss,"' in a recent review relevant mechanisms of activation granule constituents and phospholi-of tissue destruction by neutrophils, have been heretofore obscure. Third, pase products. However, as in adulthas described an intricate interaction antioxidants exert strong anti-inflam- respiratory distress syndrome wherebetween NADPH oxidase-derived ox- matory effects in a number of experi- increased alveolar capillary mem-ygen metabolites and granule-based mental models. brane permeability is often attributedtoxins that had been formulated dur- Elastase can degrade almost all to neutrophil mediation, there are sev-ing the course of millions of years of components of the extracellular ma- eral possible relationships betweenevolution. Superoxide, generated by trix, cleave immunoglobulins and com- neutrophil accumulation and the de-the neutrophil, is rapidly converted to plement and clotting factors, and at- velopment of lung pathology that re-H202. The hydrogen peroxide is con- tack intact cells.'22 It is inhibited in quire critical analysis before acceptingverted almost quantitatively by the vivo by a-proteinase inhibitor prima- a causal role for neutrophils. 2 6very abundant enzyme, myeloperoxi- rily and also by a2-macroglobulin and Cholesteroldase (constitutes up to 5% of the dry secretory leukoproteinase inhibitor.weight of neutrophils), to hypochlo- Th e a,-proteinase inhibitor forms an Brief periods of high-cholesterol in-rous acid in the following reaction: irreversible enzyme-inhibitor complex take, lasting several days to severalat a rate that approaches the diffu- weeks and leading to hypercholester-H20, + CI + H sion-controlled limit, so that the half- olemia, may cause an acute injury toyelroxidase time of elastase in vivo is about endothelium through an unidentifiedHOCI + HO. 0.6 milliseconds, and all activity is in- mechanism. Such dietary indiscretionHydroxyl radical production by the hibited in about 3 milliseconds. 23 Chlo- might also exacerbate reperfusion in-neutrophil has not been demonstrated. rinated oxidants destroy the antipro- jury in the event of myocardial is-Hypochlorous acid is the sole active teinase shield. A critical methionine at chemia. Isolated, perfused hearts fromingredient in household liquid bleach, position 358 on the a-proteinase in- rabbits that were fed normal chowand a million neutrophils can produce hibitor becomes oxidized, causing a that had been supplemented with 2%a sufficient amount to destroy 150000 2000-fold decrease in the rate of asso- cholesterol for 2 to 3 weeks were sub-Escherichia oli organisms in millisec- ciation between neutrophil elastase jected to 30-minute ischemia, followedonds. In a physiologic environment, and the modified a,-proteinase inhibi- by 3.5 hours of reperfusion 2 1 VascularHOCI reacts with primary or second- tor. As a result, the in vivo half-time of permeability (indicated by uptake andary amines to generate a complex fam- elastase increases from 0.6 millisec- clearance of iodine 125-bovine serumily of nitrogen-chlorine (N-Cl) deriva- onds to 1.2 seconds. a 2-macroglobulin albumin) and vascular resistance weretives termed chloramines': and secretory leukoproteinase inhibi- increased during reperfusion in thesetor are also oxidatively inactivated, hearts compared with those from ani-R' RNH + HOCI - R'RNCI + H20. This creates a microenvironment in mals that were fed normal chow or fedTh e question arises as to whether which elastase can attack host tissues. cholesterol-supplemented chow forHOC] and chloramines are cytotoxic in Neutrophil collagenase and gelatinase longer periods (5 to 16 weeks).vivo. Some clinical data bearing on this degrade various forms of collagen. Cholesterol supplementation for 2 toquestion emerge from experience in These enzymes, however, are released 3 weeks was also associated with in-World War I in which HOCI and chlo- in latent, inactive forms, 24 but HOCI creased vascular permeability in theramines were given in large quantities can activate them. 2 ' absence of ischemia in this study, sug-to wounded soldiers as a local irriga- It appears, then, that oxidation gesting that the altered metabolic mi-tion solution to combat infection. Mi- products, such as HOCI and chlora- lieu accompanying an abrupt increasecrobes in the wounds were killed, but mines, can combine with granule- in cholesterol consumption directly in-the HOCI and chloramine did not seem based proteinases and enable neutro- jures coronary endothelium. These ef-to cause tissue damage or interfere phils to subvert all the intrinsic and fects are independent of occlusive cor-with wound healing. 2' host-erected barriers that normally onary artery disease produced by theOxidants as a mediator of tissue serve to protect host tissue from in- atherogenic influence of chronic hy-damage tend to be short lived, react jury. By inactivation of a series of key percholesterolemia. Indeed, the directonly once, and cannot select targets. proteinase inhibitors and the simulta- toxicity to the vasculature disappearsEnzymes, stored in neutrophil gran- neous activation of latent proteinases, during protracted states of elevatedArch Neurol-Vol 47, November 1990 Reperfusion Injury- Hallenbeck & Dutka 1251


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cholesterol.Golino et al' 25 have demonstrated Lthat infarct size in acutely hypercho- C E Tlesterolemic, nonatherosclerotic rab- h L C U M R Progressive Injurybits is roughly double that of normo- Kcholesterolemic animals after a stan- Rdard ischemic injury and that the E E LS Lzones of nonreperfusion were strik- R C Aingly larger in the former group. In a Esubsequent work,'M the same groupdemonstrated that after feeding rab-bits a 2% cholesterol-enriched diet for V3 days, 30 minutes of myocardial is-chemia and 5.5 hours of reperfusion led X Regulatoryto a more than fourfold greater accu- Mechanismsmulation of indium Ill-labeled plate- o,lets in the injury zone and a larger in-farct size compared with animals re-ceiving normal chow. Goat anti-rabbitplatelet serum decreased plateletcounts by about 98% and eliminatedthe differences between hypercholes-terolemic an d normocholesterolemicanimals with respect to platelet accu-mulation, infarct size, and extent ofreperfusion impairment. Th e worksuggests that the adverse effects of Reperfusion Zoneacute hypercholesterolemia on reper-fusion injury are platelet dependent.However, monocyte adherence to en-dothelium has been observed to in-crease up to 50-fold during acute hy- Acute Ischemiapercholesterolemia, raising the possi-bility that this cell type also par- Fig 5.-A schematic overview of reperfusion injury. See text for discussion.ticipates."" CONCLUSION represented by a spring that should tors. This is the conceptually simple

As presented in this brief, general pull the tissue core back from the pro- approach, and in many trials, it ha sreview, the postulated mechanisms gressive injury position but that has produced a small positive effect. De-underlying reperfusion injury are been sprung. Th e major mechanisms, finitive therapy, however, has re-multifactoral and intricately intercon- currently ascribed to reperfusion in- mained elusive despite these efforts.nected. They are also governed by pos- jury, are shown on the face of the tis- An alternative, but conceptually moreitive and negative feedback control, sue core that undergoes progressive difficult approachthattakesaccountofcooperativity, synergism, and mainte- injury, with letters intermingled to the full network of effectors and regu-nance of homeostatic balance by emphasize that the multitude of intri- lators of reperfusion injury as a con-means of counterpoised antagonists. A cate and diverse processes encom- stellation of minor causes may be re-schematic overview of reperfusion in- passed by these mechanisms are quired to bring postischemic tissuejury is presented in Fig 5, which de- tightly interwoven as a "seamless damage to a minimum. It is possiblepicts an interpretation of the data dis- web."'"' Some of these diverse pro- that the therapeutic problem could becussed in this review and should be cesses would include coagulation, fi- attacked by exploring the regulatoryviewed as hypothetical. A core of tissue brinolysis, eicosanoid and PAF produc- mechanisms that preserve homeo-in the brain exposed to ischemia enters tion, cytokine production, rheologic static balance under normal circum-a phase of progressing injury during disturbances, granule-based toxin re- stances and by learning how to curbreperfusion after having been incited lease, adhesion receptor expression on the putative injury signals (Fig 5).by "injury signals," a theoretical con- cells, conversion of endothelium to astruct that could include eicosanoids, procoagulant state, platelet accumula- f iealth grant Re NS28225-01 anl the NavalPAF, cytokines, transcription factors tion, and, probably, many more. The Medical Research and Development (ommandthat regulate gene expression, and side of the core of tissue that under- Work Unit 61153N MR04I.X)I-I()5.conversion of the luminal surface of goes progressive injury displays a The manuscrilpt was prepared by US govern-endothelium from an anticoagulant to group of reaction properties that con- ment employeesas part of their otli.ial dutiesand,therefore, cannot be copyrighted and ma y be cop-a procoagulant membrane. In re- tribute to the complexity of the inter- iei ithout restriction.sponse, there is a perturbation of the locking events in the progressing in-homeostatic balance of many interre- jury zone. Referenceslated systems. Multiple mediators are In general, therapeutic trials have i. leissNV-l).Rosner(G.Functionalrecoveryofinvolved, and the loss of regulation tended to implicate one or more puta- cortical nearonsasrelated todegreeandidurationsets into motion a cascade of damaging tive mediators of reperfusion injury as of . ti a , I .un9 T h "wa\1f-on2. Reim~er KA, Jennings R11. he *wavefrontevents. The loss of regulation and per- a major cause of the problem and have phenomenon' of myocardial ischemic cell death.turbation of homeostatic balance are modified the activity of these media- I1:ransinural progressiin of necrosis within the

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1254 Arch Neurol-Vol 47, November 1990 Reperfusion Injury-Hallenbeck &Dutka

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