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1、MedicinalChemistry,2007,3,13-2013BiophysicalCharacterizationoftheInteractionofEndotoxinswithHemo-globins11123J?rgHowe,MalteHammer,ChristianAlexander,ManfredR?ssle,KarinFournier,3451Jean-PierreMach,ThierryWaelli,ReginaldM.Gorczynski,ArturJ.Ulmer,111,*UlrichZ?hringer,ErnstTh.Rietscheland

2、KlausBrandenburg12PPForschungszentrumBorstel,Leibniz-ZentrumfürMedizinundBiowissenschaften,Borstel,Germany;EuropeanMo-3lecularBiologyLaboratory,Hamburg,Germany;InstitutedeBiochemie,UniversitédeLausanne,Lausanne,Switzer-45land;CliniqueLaPrairie,Montreux,Switzerland;Dep.ofSurgeryandImmun

3、ology,UniversityHealthNetwork,To-ronto,CanadaAbstract:Bacterialendotoxin(lipopolysaccharide,LPS)isthemajorcomponentoftheouterleafletoftheoutermem-braneinGram-negativebacteria.Duringsevereinfections,bacteriamayreachthebloodcircuitofhumans,andendotox-insmaybereleasedfromthebacteriaduetoc

4、elldivisionorcelldeath.InparticularenterobacterialformsofLPSrepre-sentextremelystrongactivatormoleculesofthehumanimmunesystemcausingarapidinductionofcytokineproductioninmonocytesandmacrophages.VariousmammalianbloodproteinshavebeendocumentedtodisplayLPSbindingactivi-tiesmediatingnormall

5、ydecreasingeffectsinthebiologicalactivityofLPS.Inmorerecentstudies,theessentialsystemicoxygentransportationproteinhemoglobin(Hb)hasbeenshowntoamplifyLPS-inducedcytokineproductiononimmunecells.Themechanismresponsibleforthiseffectispoorlyunderstood.Here,wecharacterizetheinteractionofhemo

6、globinwithLPSbyusingbiophysicalmethods.Thedatapresented,reveal-ingthechangesofthetypeandsizeofsupramolecularaggregatesofLPSinthepresenceofHb,allowabetterunderstand-ingofthehemoglobin-inducedincreaseinbioactivityofLPS.INTRODUCTIONaddition,lowerconcentrationsofcell-freeHbareconstantlyrel

7、easedintothecirculationduetoaninherentintravascularBacterialendotoxin(lipopolysaccharide,LPS),withitshemolyticdisruptionoferythrocyteswhichcanbelargelyhydrophobicmembraneanchorlipidAconstitutesthemajorincreasedduringthecourseofsevereanemichemoglobi-lipidcomponentoftheoutermembraneofG