病理生理学病理生理学 (5).pdf

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1、Review ArticleIschemia/Reperfusion Injury followingAcute Myocardial Infarction:A Critical Issue forClinicians and Forensic PathologistsMargherita Neri,1Irene Riezzo,2Natascha Pascale,2Cristoforo Pomara,2and Emanuela Turillazzi21Section of Forensic Pathology,Morphology,Surgery and Experimental Medici

2、ne Department,University of Ferrara,Ospedale“SantAnna”,Via Fossato di Mortara 70,44121 Ferrara,Italy2SectionofForensicPathology,ClinicalandExperimentalMedicineDepartment,UniversityofFoggia,OspedaleColonnelloDAvanzo,Viale Degli Aviatori 1,71100 Foggia,ItalyCorrespondence should be addressed to Emanue

3、la Turillazzi;emanuela turillazziinwind.itReceived 4 August 2016;Revised 26 October 2016;Accepted 30 November 2016;Published 13 February 2017Academic Editor:Veronica TisatoCopyright 2017 Margherita Neri et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,which permits

4、 unrestricted use,distribution,and reproduction in any medium,provided the original work is properly cited.Acute myocardial infarction(AMI)is a leading cause of morbidity and mortality.Reperfusion strategies are the current standardtherapyforAMI.However,theymayresultinparadoxicalcardiomyocytedysfunc

5、tion,knownasischemicreperfusioninjury(IRI).Different forms of IRI are recognized,of which only the first two are reversible:reperfusion-induced arrhythmias,myocardialstunning,microvascular obstruction,and lethal myocardial reperfusion injury.Sudden death is the most common pattern forischemia-induce

6、dlethalventriculararrhythmiasduringAMI.TheexactmechanismsofIRIarenotfullyknown.Molecular,cellular,and tissue alterations such as cell death,inflammation,neurohumoral activation,and oxidative stress are considered to be ofparamount importance in IRI.However,comprehension of the exact pathophysiologic

7、al mechanisms remains a challenge forclinicians.Furthermore,myocardial IRI is a critical issue also for forensic pathologists since sudden death may occur despitetimely reperfusion following AMI,that is one of the most frequently litigated areas of cardiology practice.In this paper weexplore the lit

8、erature regarding the pathophysiology of myocardial IRI,focusing on the possible role of the calpain system,oxidative-nitrosative stress,and matrix metalloproteinases and aiming to foster knowledge of IRI pathophysiology also in terms ofmedicolegal understanding of sudden deaths following AMI.1.Intr

9、oductionAcutemyocardialinfarction(AMI)isaleadingcauseofmor-bidity and mortality in the world 1.Reperfusion strategiesare the current standard therapy for AMI 2,3.They may,however,result in paradoxical cardiomyocyte dysfunctionand worsen tissue damage,in a process known as“reperfu-sion injury”49.Isch

10、emic reperfusion injury(IRI)typi-cally arises in patients presenting with an acute ST-segmentelevation myocardial infarction(STEMI),in whom themost effective therapeutic intervention is timely and effec-tive myocardial reperfusion 7,1014.Reperfusion itselfis known as a“double-edged sword”4,15 due to

11、 thespectrum of reperfusion-associated pathologies.Outcomessubsequent to IRI accrue in a time-dependent fashion 16,beginning with oxidative stress,inflammation,intracellularCa2+overload,and rapidly proceeding to irreversible celldeath by apoptosis and necrosis 13,16.Different forms ofmyocardial IRI

12、are recognized,of which only the first twoare reversible:reperfusion-induced arrhythmias,myocardialstunning,microvascular obstruction,and lethal myocardialreperfusion injury 13.In particular,sudden death is the most common patternfor ischemia-induced lethal ventricular arrhythmias(VAs)during the acu

13、te phase of myocardial infarction 17,and it iswellknownthatreperfusionitselfcanleadtolife-threateningVAs 17 and,ultimately,induce sudden mortality.The exact mechanisms of IRI are not fully known 18.Molecular,cellular,and tissue alterations such as cell death,Hindawi Publishing CorporationMediators o

14、f InflammationVolume 2017,Article ID 7018393,14 pageshttp:/dx.doi.org/10.1155/2017/70183932Mediators of Inflammationinflammation,neurohumoral activation,and oxidative stressare considered to be of paramount importance for IRIdevelopment 10,19.However,comprehension of the exactpathophysiological mech

15、anisms of IRI 20,21 remains achallenge for clinicians 22,23,and the existence of reper-fusion injury is still a matter of debate in the scientific com-munity,essentially due to a lack of a definitive clinical doc-umentation.Many gaps still exist between experimental ani-mal models and human clinical

16、 experience,with subsequentdifficulties in translating experimental results on cardio-protectiontoclinicalpractice2224.Despitethedifficultiesthat still exist in fully comprehending myocardial IRI,earlyandaggressivereperfusionstrategiesremainthemostimpor-tant intervention and are strongly advocated.T

17、he develop-ment of ischemic conditioning strategies to limit the extentof infarcted tissue caused by ischemia/reperfusion injurymarkedly enhances the ability of the heart to withstand anischemic insult 25.Finally,myocardial IRI is a critical issue also for forensicpathologists since sudden death may

18、 occur despite timelyreperfusionfollowingAMI,thatisoneofthemostfrequentlylitigated areas of cardiology practice 26,27.In this paper we explore the literature regarding thepathophysiology of myocardial IRI,focusing on the possiblerole of the calpain system,oxidative-nitrosative stress,andmatrix metal

19、loproteinases.We discuss these mechanismswithin the broad scenario of IRI,also discussing the medi-colegal issues related to sudden deaths occurring duringthe acute phase of myocardial infarct following reperfusioninterventions.2.The Calpain SystemThe process of IRI is not yet completely understood

20、in itsunderlying pathophysiological mechanisms.Several path-wayshavebeenproposed,includingcytosolicandmitochon-drialCa2+overload,releaseofreactiveoxygenspecies(ROS),acute inflammatory response,and impaired metabolism 20,21.These alterations may collaboratively act and produceirreversible damage to i

21、schemic reperfused cardiomyocytes.The possibility that the calpain system could play arole in generating myocardial IRI has been experimentallyinvestigatedintheliterature2832,andseveralstudieshavefocused on the effects of calpain inhibitors in improvingmyocardial dysfunction in different animal mode

22、ls 3337.Calpains are a family of Ca2+-dependent nonlysosomal cys-tein proteinase localized in the cytosol in their inactive form38.Calpainactivation,whichmayoccurunderseveralcon-ditions,is thought to be a key mechanism in activating anumber of substrates such as growth factor receptors,cyto-skeletal

23、proteins,microtubulesassociatedproteins,andmito-chondria,soplayingacrucialroleincellcycle,apoptosis,anddifferentiation 3840.The calpain superfamily is complex,and more than 25calpains or calpain-like molecules have been discovered.Calpains 1 and 2 are biologically activated when they arrangeas dimer

24、 with a 30 kDa subunit.Both biologically activecalpains are usually called-calpain(calpain 1+30 kDa sub-unit)and m-calpain(calpain 2+30-kDa subunit).Theterms-calpain and m-calpain indicate,respectively,themicromolarandmillimolarCa2+concentrationsrequiredfortheiractivation19.Calpainsmayappearinthefor

25、mofboth“ubiquitous”isoenzymes that are present in almost all cells(suchas-calpain,m-calpain,andcalpains5,7,10,13,and15)and“tissuespecific”calpainsexpressed onlyinspecialtissuesand cells,such as calpains 3 and 6 and others 31.In brief,it has been hypothesized that,under physio-logical conditions,inac

26、tive calpains are stored in cellularcytosolandboundinasubstratecompetitivemannertotheirendogenous inhibitor calpastatin.The elevation of intracel-lularcalciumlevelsisthekeytothecalpainactivationprocess.Calpainconformationalchangespermititstranslocationintocellular membrane,where phospholipids reduce

27、 the Ca2+threshold for calpain activation or close the Ca2+channelsleading up to protein activation 41.Several pathologicalcardiac events are associated with an imbalance of calciumhomeostasis related to myocardial ischemia/reperfusioninjury 2931.Experimental studies on isolated perfusedmammalian he

28、arts demonstrated an increase in intracellularCa2+concentrations in response to ischemia/reperfusion 31,41.Myocardial ischemia favours intracellular ion accumula-tion(sodium,calcium)till dropping in pH and tissue acido-sis.Reperfusionevokesrapidalterationsinionfluxandinter-acts with ischemia in alte

29、ring the physiology of ion exchange42.Among others,a final result of the dangerous inter-play between ischemia and reperfusion is intracellular cal-cium overload.The kinetics of calpain activation are not completelyunderstood,and whether or not translocation to the sar-colemma is needed for calpain

30、activation during IRI remainsundetermined43.Intheirelegantexperiment,Hernandoetal.37 suggested that calpain translocation to the cardiomy-ocytesmembranesduringischemiaisindependentofitsacti-vation since intracellular acidosis occurring during ischemiais likely to inhibit calpain activation.As intrac

31、ellular pH nor-malizesfollowingreperfusion,calpainactivationoccurs.Des-pitetranslocation,calpainseemstoremaininactiveevenafter60minutesofischemiaandonlyonreperfusionisitactivated37.Activated calpain has a number of substrates such asgrowth factor receptors,cytoskeletal proteins,microtubulesassociate

32、d proteins,and mitochondria,thus playing a crucialrole in the processes of cell cycle,apoptosis,and differentia-tion,negatively affecting cardiomyocyte function.Firstly,the calpain system is part of the integrated prote-olyticsystemwhichiscrucialtothemaintenanceofthestruc-ture and function of the ca

33、rdiac sarcomere.An imbalance ofthis system is the key to the sarcomeric dysfunction linkedto several cardiovascular diseases,including hypoxia,IRI,myocardial infarction,and end-stage heart failure.Proteindegradation(proteolysis)within cardiac sarcomere is regu-lated mainly by three systems:the ubiqu

34、itin proteasome sys-tem(UPS);autophagy/lysosomal degradation;and the cal-pain system 44.Degradation of myofibrillar proteinsinvolved in the contractile process is an effect of calpain acti-vation.The degradation process following IRI involves eitherstructural or regulatory proteins of contractile ap

35、paratus.In vitro study 45 showed that many of these proteins areMediators of Inflammation3ReperfusionCalpain system activationDegradation ofstructural proteinsand increased sarcolemmal fragilityApoptosisactivation and mitochondriadamageProteolysis ofmyofibrillar proteins/loss/disorganization of T-tu

36、bules structureIschemiaMembrane damage and ruptureAlteration of myofibrillarcontractilityCell deathOxidative stress Heart failureCa2+overloadCa2+overloadpHpH recoveryFigure 1:Schematic representation of calpain activation during myocardial IRI.Ca2+overload and pH recovery in reperfusion phase arecru

37、cialintheactivationofthecalpainsystem.Increasedsarcolemmalfragilitymayleadtomembraneruptureandcelldeath.Inaddition,boththedeath-receptorandmitochondrialmediatedapoptoticpathwaysseemtobeaffectedbycalpainactivation.Thedegradationofmyofibrillarproteins and the loss/disorganization of T-tubules structur

38、e are key factors in post-MI heart failure development.potential targets of activated calpains,thus contributing tothe development of postischemic injury in the human myo-cardium.Several experimental studies demonstrated that theloss/disorganization of T-tubules structure is a key factorin heart fai

39、lure development 4648.Calpain-mediateddisruption of T-tubules integrity through the proteolysis ofjunctophilin is demonstrated to be one of the major factorsinvolved in an experimental model of cardiac muscle failure49,50.Calpain deregulation is known to be an effective mech-anism of apoptosis induc

40、tion in cardiac sarcomeres throughdifferent pathways 5153,and apoptosis of myocardial cellsis considered an important mechanism of IRI 5456.Conclusively,an uncontrolled activation of calpain hasbeenfoundtobeimplicatedinthepathophysiologyofseveralcardiovascular disorders 57 including myocardial IRI 5

41、8,and the inhibition of calpains has been shown to attenuatemyocardial stunning and reduce infarct size after ischemiareperfusion59(Figure1).However,theexactroleofcalpainin acute myocardial IRI remains controversial 60.3.Oxidative Stress and MitochondriaAn oxidant and antioxidant imbalance(oxidative

42、 stress)favours the accumulation of oxidants,from both increasedROS production and decreased ROS scavenging ability,thusleadingtocellulardamageinthecardiomyocytes61.Oxida-tive stress is often associated with elevated levels of ROS orreactive nitrogen species(RNS)in the cellular and subcel-lular leve

43、ls 61,leading to proteins,lipids,and DNA dam-age 62.Furthermore,in cardiomyocytes,increased ROS/RNS levels can induce alterations of proteins involved inexcitation-contraction coupling with increased susceptibilityto proteolysis 6265.In the first few minutes IRI,and especially myocardialreperfusion,

44、induces a high production of ROS by a varietyof sources 6669.Since Arroyo et al.provided direct evi-dence of ROS formation during myocardial ischemia andpostischemic reperfusion by trapping these free radicalsusing nitrone DMPO 70,several preclinical and clinicalstudies 7174 have demonstrated the po

45、tential cardiopro-tective value of antioxidants.While small amounts of ROScould result in cardioprotection via preconditioning 75,theexcessive production of ROS during reperfusion seems espe-cially important in inducing injury.Mechanisms leading up to the dysfunction and the initialsources of ROS du

46、ring IRI are not completely clear 76.Nitric oxide(NO)production is considered a key factorin IRI.NO is an important bioactive substance whichplays an important role in the regulation of normal bodyfunction and disease occurrence,and it is recognized asan ubiquitous signalling molecule with a multitu

47、de of bio-logical actions and targets.Signalling may involve directreactions between NO and a molecular target or can occurthrough indirect reactions of secondary ROS 77.In fact,actions of NO are multifaceted,and its interactions withoxygen or oxygen-related reactive intermediates(e.g.,super-oxide)y

48、ield numerous RNS and ROS.These account formost of the so-called indirect effects attributed to NOthrough oxidation,nitrosation,and nitrate reactions referredto as oxidative,nitrosative,and nitrative stress,respectively.The physiological production of NO in the heart maintainscoronary vasodilator to

49、ne and inhibits platelet aggregationandneutrophilandplateletadhesion,soperforminganactive4Mediators of Inflammationroleincardioprotection7880.Beyonditsbeneficialeffects,it has been speculated that NO excess can induce cellularinjury either due to direct toxicity 81,82 and to the reactionwith superox

50、ide(O2)to form the potent oxidant peroxynit-rite(ONOO2)83 which in turn exerts cytotoxicity via itsreaction with a variety of molecular targets 84,85.Theformationofhighlyreactivespecies,suchasperoxynitrite,isapossiblemechanismbywhichNOelicitsitsdangerouseffects83.MuchaboutNObiologicalactionsremainsc