HMGB1 and Histones Play a Significant Role in Inducing Systemic Inflammation and Multiple Organ Dysfunctions in Severe Acute Pancreatitis

Re iew A icle HMGB1 and His ones Play a Signi ican Role in Inducing Sys emic In lamma ion and Mul iple O gan Dys unc ions in Se e e Acu e Panc ea i is Runkuan Yang,1,2,3 Jy ki Tenhunen,1,4 and To Inge Tonnessen3,5 1Depa men o In ensi e Ca e Medicine, Tampe e Uni e si y Hospi al, Uni e si y o Tampe e, 10 Bioka u, 33014 Tampe e, Finland 2Depa men o C i ical Ca e Medicine, Uni e si y o Pi sbu gh Medical School, 3550 Te ace S ee , Pi sbu gh, PA 15261, USA 3Depa men o Eme gencies and C i ical Ca e, Oslo Uni e si y Hospi al, 4950 Nydalen, 0424 Oslo, No way 4Depa men o Su gical Science, Anes hesiology and In ensi e Ca e Medicine, Uppsala Uni e si y, 751 85 Uppsala, Sweden 5Ins i u e o Clinical Medicine, Uni e si y o Oslo, Blinde n, 0316 Oslo, No way Co espondence should be add essed o Runkuan Yang; unkuan[email p o ec ed] Recei ed 6 Oc obe 2016; Accep ed 13 No embe 2016; Published 21 Feb ua y 2017 Academic Edi o : Jean-Ma c Ca aillon Copy igh © 2017 Runkuan Yang e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Se e e acu e panc ea i is (SAP) s a s as a local in lamma ion o panc ea ic issue ha induces he de elopmen o mul iple ex apanc ea ic o gans dys unc ion; howe e , he unde lying mechanisms a e s ill no clea . Ischemia- epe usion, ci cula ing in lamma o y cy okines, and possible bile cy okines signi ican ly con ibu e o gu mucosal inju y and in es inal bac e ial ansloca ion (BT) du ing SAP. Ci cula ing HMGB1 le el is signi ican ly inc eased in SAP pa ien s and HMGB1 is an impo an ac o ha media es (a leas pa ly) gu BT du ing SAP. Gu BT plays a c i ical ole in igge ing/inducing sys emic in lamma ion/sepsis in c i ical illness, and p o ound sys emic in lamma o y esponse synd ome (SIRS) can lead o mul iple o gan dys unc ion synd ome (MODS) du ing SAP, and sys emic in lamma ion wi h mul io gan dys unc ion is he cause o dea h in expe imen al SAP. The e o e, HMGB1 is an impo an ac o ha links gu BT and sys emic in lamma ion. Fu he mo e, HMGB1 signi ican ly con ibu es o mul iple o gan inju ies. The SAP pa ien s also ha e signi ican ly inc eased ci cula ing his ones and cell- ee DNAs le els, which can e lec he disease se e i y and con ibu e o mul iple o gan inju ies in SAP. Hepa ic Kup e cells (KCs) a e he p edominan sou ce o ci cula ing in lamma o y cy okines in SAP, and new e idence indica es ha hepa ocy e is ano he impo an sou ce o ci cula ing HMGB1 in SAP; he e o e, ea ing he li e inju y is impo an in SAP. 1. In oduc ion Acu e panc ea i is (AP) is a ela i ely common disease, i s se e e o mispo en ially a al,andSAPisassocia edwi h high mo ali y, anging om 15 o 40% [1–8]. AP s a s as a local in lamma ion o panc ea ic issue ha induces he de elopmen o mul iple ex apanc ea ic o gans dys unc ion including acu e lung inju y [8–10], gene al endo helial ba ie dys unc ion, li e inju y, and gu ba ie dys unc ion [2, 6, 8]; sys emic in lamma ion is hough o be he key link o mul iple o gan dys unc ion (MOD) in SAP [11, 12] and gu BT plays a c i ical ole in igge ing/inducing sys emic in lamma ion [13, 14]; howe e , he unde lying mechanism o BT in SAP is s ill poo ly unde s ood. The in lamma o y cy okinesplayac ucial olein hepa hogenesiso SAP [6,7,15,16]and hela ep oin lamma o ycy okineHMGB1is pa icula ly impo an in SAP [17, 18], because he ci cula ing HMGB1 le els can e lec he disease se e i y and a e po en in augmen ing sys emic in lamma ion [17, 18], and eme ging e idence shows ha HMGB1 is also an impo an ac o ha media es 85% o he gu BT in ace aminophen hepa o oxici y [19]; he e o e, i is possible ha HMGB1 also media es BT in SAP. Excep HMGB1, new in es iga ions show ha ex acel- lula his ones and DNAs migh also signi ican ly con ibu e o mul iple o gan inju y du ing SAP [20–23]. Because hepa ic KCs a e he p edominan sou ce o ci cula ing in lamma o y cy okines (including HMGB1) in SAP [8], and new e idence indica es ha hepa ocy e is ano he impo an sou ce o Hindawi In e na ional Jou nal o Inflamma ion Volume 2017, A icle ID 1817564, 6 pages h ps://doi.o g/10.1155/2017/1817564 2In e na ional Jou nal o In lamma ion ci cula ing HMGB1 in SAP [15, 16]; he e o e, he in lamed li e is an impo an con ibu o o he ci cula ing HMGB1 and he li e is a p omising he apeu ic a ge o p e en BT and sys emic in lamma ion du ing SAP. This manusc ip ocuses on he new de elopmen in gu BT and p o ides e idences o show ha HMGB1, his ones, and DNAs migh signi ican ly con ibu e o sys emic in lamma ion and mul i- ple o gan inju y du ing SAP. 1.1. Ischemia-Repe usion, Ci cula ing In lamma o y Cy ok- ines, and Possible Bile Cy okines Con ibu e o Gu Ba ie Dys unc ion in SAP. Gu ba ie dys unc ion is equen ly seen in SAP [6, 11, 24, 25] and cla i ying he unde lying mechanisms is impo an because he in es ine is he bigges ese oi o bac e iain hebodyandleakageo bac e ia o mic obial p oduc s, no ably LPS, om he in es inal lumen in o he sys emic ci cula ion, leads o ini ia ion o ampli ica ion o a sys emic in lamma ion and MOD [26]. In es inal ischemia- epe usion signi ican ly con ibu es osmallin es inalinju ydu ingSAP[27,28]byinducing gu mucosal inju y and a ec ing gu muscula laye o impai gu mo ili y, which is equen ly seen in SAP [14], and he educed in es inal mo ili y signi ican ly con ibu es o dis up ed in es inal mic o lo a and BT [14]. The ci cula ing in lamma o y cy okines including TNF- 𝛼, IL-6, and HMGB1 also con ibu e o gu mucosal inju y [29–32], among hese in lamma o y cy okines, ex acellula HMGB1 igge s and sus ains he in lamma o y esponse by inducing cy okine elease and by ec ui ing leucocy es [33]. Howe e , HMGB1 unde goes ex ensi e pos ansla ional modi ica ions, in pa icula ace yla ion and oxida ion, which signi ican ly modula e he unc ions o HMGB1 [33, 34]. High le els o se um HMGB1, in pa icula o he hype ace yla ed and disul ide iso o ms, a e sensi i e disease bioma ke s [33], and SAP pa ien s ha e signi ican ly inc eased se um HMGB1 le els [35, 36], which can e lec he se e i y o gu ba ie inju y [35]. The ci cula ing HMGB1 con ibu es o gu mucosal hype pe meabili y and induces e iden BT du ing hemo hagic shock and epe usion [37], and exogenous HMGB1 injec ion is able o induce gu hype pe meabili y and BT in no mal mice [29]. Excep om he ci cula ing HMGB1, bile HMGB1 migh also signi ican ly con ibu e o in es inal mucosa inju y and induces e iden BT in SAP because SAP pa ien s ha e signi i- can ly inc eased ci cula ing LPS le els [38], and LPS injec ion educes40%o bile lowinno mal a s[31];adequa e bile is impo an o main ain gu epi helial igh junc ion and in es inal bac e ial homeos asis [31] and dec eased gu luminal bile olume no only impai s in es inal igh junc ion, bu also changes in es inal bac e ial homeos asis o acili a e BT [31]. In addi ion, LPS injec ion ( o no mal animals) ma kedly inc eases bile TNF-𝛼and HMGB1 le els, and he endo oxemic bile can induce gu mucosal hype pe meabili y ande iden BTinno malmice[31],andneu aliza iono bile HMGB1 can e e se endo oxemic bile induced in es inal mucosal hype pe meabili y and BT in no mal mice [31], sugges ing ha bile HMGB1 is able o cause gu mucosal inju y and in es inal BT. 1.2. HMGB1 Plays a Signi ican Role in Media ing BT in SAP. SAP induces signi ican small in es inal inju y [27, 28], and he ailu e o gu ba ie is associa ed wi h BT [27], which is e iden in SAP [6, 24, 25]. SAP pa ien s ha e signi ican ly inc eased se um LPS le el, which is likely de i ed om he gu lumen o om ansloca ed in es inal bac e ia [38]. 68.8% o he SAP pa ien s ha e bac e aemia and hese bac e ia ha e been es ed as gu -de i ed oppo unis ic pa hogens [24], which likely de i e om small bowel a he han om he colon [25]. The e o e, i is impo an o iden i y he key ac o ha media es in es inal BT in SAP. Gu bac e ia can adhe e o he inju ed in es inal mucosa ha is necessa y bu no su icien o induce gu BT in which HMGB1 and o he unknown ac o s a e also needed, because e idence shows ha exogenous HMGB1 injec ion can induce gu mucosal inju y and e iden BT in no mal mice [29], and HMGB1 also con ibu es o gu ba ie dys unc ion in a s wi h SAP [32]; blockade o HMGB1 educes 85% o BT bu does no signi ican ly imp o e gu mucosal inju y du ing ace aminophen hepa o oxici y [19]; simila ly, e hyl py u a e (EP), which is a HMGB1 inhibi o [39], educes 80% o he gu BT bu did no signi ican ly dec ease in es inal mucosal hype pe meabili yinale halSAPanimalmodel[6]; his BT-inhibi ion e ec is associa ed wi h EP inhibi ing 80% o he hepa ic issue HMGB1 elease [15]. These e idences indica e ha HMGB1 migh media e gu BT in SAP, and his hypo hesis is con i med by he ollowing expe imen : neu aliza ion o HMGB1 dec eased 70% o he gu BT (4252 ±205 CFU/g o he sham an ibody g oup e sus 1235 ± 41 CFU/g o he an i-HMGB1 g oup, esul s a e mean ± SEM, 𝑛=6 o each g oup, unpublished da a) bu did no educe gu mucosal hype pe meabili y in ano he commonly used mu ine SAP model (7 hou ly 50 𝜇g/kg in ape i oneal injec ions o ce ulean and a single in ape i oneal injec ion o 4 mg/kg Esche ichia coli lipopolysaccha ide). These da a indica e ha in es inal mucosal inju y is essen ial bu no su icien o gu BT du ing SAP; HMGB1 plays a signi ican ole in media ing (a leas pa ly) gu BT in expe imen al SAP and BT is likely an ac i e “ anscellula ” p ocedu e. 1.3. Gu BT Induces/T igge s Sys emic In lamma ion and Sep- sis. Gu BT no only con ibu es o panc ea ic in ec ion [14, 25], bu also induces/ igge s sys emic in lamma ion/sepsis in c i ical illness [13, 14], and he p o ound sys emic in lam- ma ioncanlead oMODandmo ali yinSAP[9,14,27, 40]. This is one o he impo an unde lying mechanisms ha SAP equen ly a ec s ex apanc ea ic o gans [3, 6], and he incidence o MOD in SAP is no a ailable bu ce ainly highe han he 20–30% o mo ali y a e in SAP [3]. Sys emic in lamma ion wi h mul io gan dys unc ion is he cause o dea h in a mu ine liga ion-induced SAP, and sys emic in lam- ma ion and MOD can lead o he p eponde ance o mo ali y (75%) in his le hal SAP model [11] while bile duc liga ion does no ha e mo ali y [11]. The e o e, he gu is hough o ac as he s a e o SIRS [27] and HMGB1 is an impo an ac o ha links gu ba ie dys unc ion and MOD du ing SAP. In e na ional Jou nal o In lamma ion 3 1.4. The Li e I sel Plays an Impo an Role in BT in SAP. AP equen ly a ec s he li e [6, 15] ha plays an impo an ole in BT du ing SAP by i ue o i s unique s uc u e and immune su eillance unc ion [14, 41]. The li e is he la ges o gan in he body, hepa ocy es accoun o 70–80% o he hepa ic cy oplasmic mass and nonpa enchymal cells make up 20–30% o he hepa ic cy oplasmic mass [41]. Among he nonpa enchymal cells, KCs, sinusoidal endo helial cells, and he na u al kille (NK) lymphocy es exe cellula de ence unc ions o he whole body bu also o he li e i sel [41].Theli e hasala genumbe o immunecells ha can be apidly expanded in esponse o in ec ion o inju y by ec ui ing leukocy es om he ci cula ions [42]. SAP equen ly inju es he li e [6, 15, 16, 40] and impai s he phagocy ic unc ion [14, 40]; he impai ed hos de ence ails o clea egional lymph nodes and esul an ly acili a es BT [14, 40]. 1.5. HMGB1, Ex acellula His ones, and DNAs Con ibu e o Mul iple O gan Inju ies. Abou 20–30% o acu e panc ea i is pa ien s de elop SAP in clinical p ac ice; he mo ali y a e in SAP is 20–30% [3]; howe e , mos o he SAP ela ed mo ali y is no due o panc ea ic inju y i sel ; sys emic in lamma ion wi h mul io gan dys unc ion is he cause o dea h [11]. Ea ly in lamma o y cy okines a e ce ainly in ol ed in he pa hogenesis o SAP; howe e , due o he na ow window ime o he ea ly cy okines in clinic, he clinical signi icance o he ea ly in lamma o y cy okines is limi ed. A en ion should be ocused on he la e in lam- ma o y cy okines such as HMGB1 and he newly ecog- nizedhis onesbecause hesedamageassocia edmolecula pa e ns (DAMPs) ha e much wide window ime o ea he pa ien s and hese DAMPs also signi ican ly con ibu e o mul iple o gan inju ies. The ci cula ing HMGB1 le el is signi ican ly highe in SAP pa ien s han in pa ien s wi h mild panc ea i is [43]; he se um HMGB1 le els a e highe in SAP pa ien s wi h o gan dys unc ion and in ec ion han in pa ien s wi hou o gan dys unc ion o in ec ion [36]; he se um HMGB1 le els in nonsu i o s a e highe han hose in su i o s [36]; se um HMGB1 le els a e posi i ely co ela ed wi h disease se e i y sco es [36]. Panc ea ic issue HMGB1 le els a e signi ican ly inc eased in expe imen al SAP [44]; HMGB1 p omo es he pa hogenesis o panc ea i is [39, 45], and inhibi ing HMGB1 he apy amelio a es he panc ea ic inju y [46]. HMGB1 con ibu es o li e inju y in ischemia- epe usion [47]. Exogenous HMGB1 injec ion is able o induce li e inju y in no mal mice [29]. HMGB1 impai s hep- a ocy e egene a ion du ing ace aminophen hepa o oxici y and blockade o HMGB1 imp o es hepa ocy e egene a ion in ace aminophen o e dose-induced a al li e inju y [48]. An i-HMGB1 ea men p o ec s agains APAP hepa o oxic- i y in a s [49]. HMGB1 also con ibu es o enal ischemia- epe usion inju y [50], sepsis-induced kidney inju y [51], and se e e acu e panc ea i is ela ed kidney inju y [52]. HMGB1 is also ound o signi ican ly con ibu e o hemo - hagic shock ela ed acu e lung inju y (ALI) [53], hypoxia- induced ALI [54], and se e e acu e panc ea i is ela ed ALI [55]. The ex acellula his ones a e ano he g oup o impo an DAMPs molecules [56], which a e oxic o hos cells and elici immunos imula o y e ec ha esul s in issue damage and in lamma ion [56, 57]. The nec o ic issue/ he dying cells elease HMGB1 and his ones as DAMPs [57]; he e o e, ci cula ing his ones a e signi ican ly inc eased in bo h SAP pa ien s and expe imen al animals wi h SAP [20–23] and he ci cula ing his ones le els e lec he disease se e i y in expe imen al AP [21]. The on-admission ci cula ing nucleosome (con aining DNA and his ones) le els can p edic o gan dys unc ion du ing he hospi aliza ion o AP pa ien s [20], sugges ing ha ex acellula his ones migh con ibu e o mul iple o gan dys unc ions in SAP. Reduced panc ea ic inju y is associa ed wi hdec easedhis ones3andhis one4le elsin hepanc eas in esponse o au ochola e challenge [23], sugges ing ha his ones a e associa ed wi h panc ea ic inju y du ing SAP. The ex acellula his ones kill endo helial cells and a e one o he majo media o s o dea h in sepsis [58]. Ex acellula his ones con ibu e o wo di e en acu e a al li e inju y models [57]; TLR2 and TLR4 a e he majo ecep o s o ex acellula his one media ed s e ile in lamma ion, issue inju y, and o gan ailu e in acu e li e ailu e (ALF) [57]; neu aliza ion o his ones can amelio a e hese wo di e en a al li e inju y models in mice [57]. Ex acellula his ones can induce mic o ascula endo helial inju y and he TLR2/4- media ed in lamma ion can lead o acu e ubula nec osis in acu e kidney inju y (AKI) [59, 60]. Ex acellula his ones inju e endo helial cells causing mic o ascula h ombosis and hemo hage in acu e lung inju y (ALI) [61]. His ones also con ibu e o s oke in acu e b ain inju y, and blockade o his ones can educe in a c size [62]. His one H4 and inc eased ci cula ing neu ophil ex acellula aps (NETs) ac i a e pla ele s, which igge pla ele agg ega ion and clo ing ha esul in mic o ascula h ombosis and ascula and pa enchymal inju y in sepsis [57, 58, 60]. The e o e, ex acellula his ones con ibu e o he mic o ascula com- plica ions o sepsis, small essel asculi is, acu e a al li e inju y, acu e kidney, and acu e lung inju ies [58, 60]. Cell- ee plasma DNA is signi ican ly inc eased in SAP pa ien s [20, 22] and in expe imen al animal wi h SAP [22]. Damaged cells om SAP can elease nucleosomes, which con ain DNA and his ones, in o he ci cula ion o p omo e in lamma ion, and he ci cula ing nucleosomes le els can p edic AP pa ien s who p esen no clinical signs o o gan dys unc ion on admission and a e bound o de elop o gan dys unc ion du ing hospi aliza ion [20], sugges ing ha DNA/o his ones likely play a signi ican ole in he de elopmen o o gan dys unc ion du ing SAP. Neu ophils play an ac i e ole in he de elopmen o AP [22]. Excep he sec e ion o an imic obial compounds, ac i a ed neu ophils elimina e in ading mic oo ganisms by expelling nuclea DNA and his ones o o m ex acellula web-like s uc u es called neu ophil ex acellula aps (NETs) [22]. NETs o m in he panc eas in a mu ine SAP model; addi ion o NETs and his ones o he acina cells induces ypsin o ma ion and ac i a es he signal ansduce and ansc ip ion [22]. NETs a e able o ac i a e pla ele s leading o h ombosis and he majo con ibu o o his p ocess is his one 4 [52]. NETs 4In e na ional Jou nal o In lamma ion con ibu e o o gan dys unc ion in pa ien s wi h in ec ious diseases and egula e o gan in lamma ion and inju y in mice wi h AP [22]. SAP pa ien s ha e inc eased plasma le els o NETs [22]. Adminis a ion o DNase 1 ( o deple e DNAandNETs)dec easesci cula ingHMGB1le eland educes neu ophil in il a ion and issue damage in he in lamed panc eas and lung [22], sugges ing ha DNA also signi ican ly con ibu es o he de elopmen o SAP. 1.6. The In lamed Li e Is an Impo an Sou ce o Ci cula ing HMGB1andHasanImpai edCapaci y oClea His ones in SAP. P oin lamma o y media o s a e hough o play a c ucial ole in he pa hogenesis o SAP [6, 8, 15, 16, 63, 64]. The amoun o cy okines eleased om he li e ep esen s abou 50% o he o al cy okine con en in he body [64], sugges ing ha he li e is he majo con ibu o o he ci cula ing cy okines. KCs a e he la ges numbe o issue esiden mac ophages in he body and a p edominan sou ce o ci cula ing in lamma o y cy okines in SAP [8], and KCsplayamajo oleinampli yingsys emicin lamma ion du ing AP [11, 12, 64–68]. Excep KCs, eme ging e idence is showing ha hepa ocy e is ano he impo an sou ce o ci cula ing HMGB1 in wo di e en expe imen al SAP models [15, 16]: especially in his iple-hi le hal SAP model, he in lamed li e eleases nea ly 90% o he hepa ic issue HMGB1 (de ec ed by li e issue whole cell lysis) [15]. EP is a po en HMGB1 inhibi o ha amelio a es SAP ia he educed se um HMGB1 le el [17], which is po en in aug- men ing SIRS in SAP [17, 18]. EP is also ound o amelio a e in es inal ba ie dys unc ion by educing he ileal mucosal HMGB1 exp ession [32]. EP no only inhibi s LPS-s imula ed mac ophages o elease TNF-𝛼and HMGB1 [69], bu also inhibi s he in lamed li e o elease bo h ea ly (TNF-𝛼,IL- 6) and la e (HMGB1) in lamma o y media o s du ing SAP [15, 16] and esul an ly amelio a es he SAP ela ed mul iple dis an o gans inju ies (including he li e inju y) [6, 15–18]. These e idences indica e ha bo h KCs and he hepa ocy es a e an impo an sou ce o ci cula ing HMGB1 in SAP, and hein lamedli e migh playac i ical olein he ansla ion o panc ea ic inju y in o sys emic in lamma ion and MOD. In addi ion, he li e is an impo an o gan o apidly clea ex acellula his ones [21]; howe e , SAP can induce se e e li e inju y and impai i s capaci y o clea ing his ones, and hiscanlead o heinc easedci cula inghis onesle els, which can signi ican ly con ibu e mul iple o gan inju y as desc ibed abo e. The e o e, he li e could be a p omising he apeu ic a ge o ea SAP. 2. Conclusions Inc eased ci cula ing HMGB1, his ones, and cell- ee DNAs le els in SAP pa ien s migh play a signi ican ole in con- ibu ing o sys emic in lamma ion and mul iple o gan inju y du ing SAP. HMGB1 is an impo an ac o ha migh link gu BT and sys emic in lamma ion in SAP. The in lamed li e is an impo an sou ce o ci cula ing HMGB1 and ea ing he li e inju y is impo an in SAP. Compe ing In e es s The au ho s decla e ha hey ha e no compe ing in e es s. Acknowledgmen s This in es iga ion was suppo ed by Sou h-Eas e n No way Regional Heal h Au ho i y, G an no. 2013121. Re e ences [1]M.Yousa ,K.McCallion,andT.Diamond,“Managemen o se e e acu e panc ea i is,” B i ish Jou nal o Su ge y, ol.90,no. 4, pp. 407–420, 2003. [2] R. Hegazi, A. Raina, T. G aham e al., “Ea ly jejunal eeding ini ia ion and clinical ou comes in pa ien s wi h se e e acu e panc ea i is,” Jou nal o Pa en e al and En e al Nu i ion, ol.35, no. 1, pp. 91–96, 2011. 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