Rev. Bras. Hematol. Hemoter. vol.38 número1

rev bras hematol hemoter. 2016;38(1):55–57

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Special

article

Hemolytic

vascular

inflammation:

an

update

Nicola

Conran

_,

_Camila

_Bononi

_Almeida

a_{UniversidadeEstadualdeCampinas(UNICAMP),Campinas,SP,Brazil}

b_{InstitutoIsraelitadeEnsinoePesquisaAlbertEinstein(IIEPAE),SãoPaulo,SP,Brazil}

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Articlehistory:

Received6October2015 Accepted6October2015

Availableonline28November2015

Intravascularhemolysiscanoccur inanumberofdiseases, includingsepsis,malariaandthehemolyticanemias[sickle cell disease (SCD), paroxysmal nocturnal hemoglobinuria, etc.],aswellasfollowingcertaineventssuchasmismatched transfusions.Thepathophysiologicalsignificanceof intravas-cularhemolysis had been largely ignoredin diseases such asSCDsaveforitseffectonredcellnumbers,however, rel-ativelyrecent studies haveshed lightonthe majoreffects thathemolyticprocesseshaveonvascularbiology,particularly onthe endothelium,inflammatoryprocessesandoxidative stress.

Under normal circumstances, hemoglobin (Hb) is con-tainedintheredbloodcells(RBCs),andemployedprimarily foroxygen transport. However,the destruction of RBC (i.e. hemolysis)resultsintherelease ofHbinto thecirculation. Ifthis hemoglobinisnotneutralizedimmediatelyinto less toxicmetabolitesbyspecializedscavengerproteins,suchas haptoglobin and hemopexin, as canoccur whenextensive hemolysisoverwhelms innate protective mechanisms, this cell-freeHbcauseschaos.1_{Thepotentialextentofthis}

dam-agewasperhapsfirstrecognizedwhenReiteretal.2_showed

that the decompartmentalization of Hb into the plasma significantlyimpairsvascularnitric oxide(NO) bioavailabil-ity, potentially facilitating vasoconstriction and alterations

∗ _{Correspondingauthorat:CentrodeHematologiaeHemoterapia,UniversidadeEstadualdeCampinas(Unicamp),RuaCarlosChagas,}

480,BarãoGeraldo,13081-970Campinas,SP,Brazil. E-mailaddress:[email protected](N.Conran).

in blood flow, as well asinducing endothelial dysfunction and plateletactivation.3,4 _{Whilethe contributionof}

hemol-ysisandsubsequentNOdepletiontomanifestationsofSCD, suchaspulmonaryhypertension,hasbeendisputed,5_more

recent evidencehashighlighted the significanteffects that intravascularhemolysishasoninflammatoryprocesses.The inductionofacutehemolyticeventsinC57BL/6mice(using intravenouswaterinjections,resultinginplasmalevelsof cell-freeHbthatweresimilartothoseseeninmicewithSCD)was foundtoinducearapidand extensivesystemicand vascu-larinflammatory response(within15min).Thisispossibly mediatedbyvascularNOconsumption,andleadstoextensive systemicinflammation(Figure1)andleukocyterecruitment tothebloodvessels.6_{Giventheevidencethatinflammation}

andleukocyteadhesiontotheendotheliumcaninitiateand propagatevaso-occlusiveprocesses,7,8_{itisreasonableto}

con-cludethatvascularinflammatoryprocessesthataretriggered byacuteintravascularhemolyticeventsmaybeof pathophy-siologicalsignificanceinSCDaswellasintheotherdiseases ormedicaleventsinwhichtheyoccur.

Once oxyhemoglobin hasreacted withNO inthe blood vessel,Hb-Fe3+_{isformedandcanaccumulatebothinthe}

cir-culation andintissues.9 _{In asecondaryHb-mediatedtoxic}

mechanism,Hb-Fe3+_{releasesdamaginghemin,ahydrophobic}

http://dx.doi.org/10.1016/j.bjhh.2015.10.004

56

C57BL/6

Saline Saline

High

Low H₂O

SCD mouse

Figure1–Quantificationofsystemicinflammationinvivo_{usingtheIVISLuminaSystem}®_{(CaliperLifeSciences,MA).} Imagesobtained15minafterintravenousinjectionsofsalineorwater(150␮L)inC57BL/6miceandachimericsicklecell

diseasemouse.Achemiluminescentprobe(XenoLightRedijectInflammationProbe;PerkinElmer,MA)wasinjectedinthe

mousetoquantifymyeloperoxidaseproductionofactivatedphagocytesandneutrophils.Similardatawereoriginally reportedinreference6.

moleculeshowntoinduceneutrophilextracellulartrap(NET) production, stimulate inflammasome formation and cause toll-like receptor (TLR)-4-mediated vaso-occlusion in mice withSCD, as well as lipoprotein oxidation.10–13 _These

sec-ondaryinflammatoryandoxidativeeffectsofheminappear tooccurinalessimmediate,6_{butprobablymoresustained}

manner,causingtissuedamageandendothelialdysfunction, aswellassustainingleukocyteactivationinthebloodvessels.9

Hemolysis,therefore,representsamajordisease mecha-nismandfailuretoneutralizeHbafteritsreleasefromtheRBC canresultinvascularinflammationandorgandysfunction, potentially contributingtoclinical complications that have beenassociatedwithhemolyticdiseases,suchaspriapism, pulmonaryhypertensionandlegulcers.14

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

TheauthorsaregratefultoLucasEduardoBotelhodeSouza and Prof.Dr. Dimas Tadeu Covasfor assistance with IVIS experiments depicted herein. The IVIS experiments were fundedbyFAPESP(grants2008/50582-3;11/50959-7[CBA]).

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