Evidence for Oxidative Stress and Defective Antioxidant Response in Guinea Pigs with Tuberculosis 英文参考文献.docVIP

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Evidence for Oxidative Stress and Defective Antioxidant Response in Guinea Pigs with Tuberculosis 英文参考文献.doc

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Evidence for Oxidative Stress and Defective Antioxidant Response in Guinea Pigs with Tuberculosis 英文参考文献

EvidenceforOxidativeStressandDefectiveAntioxidant ResponseinGuineaPigswithTuberculosis GopinathS.Palanisamy,NatalieM.Kirk,DavidF.Ackart,CrystalA.Shanley,IanM.Orme,RandallJ. Basaraba* DepartmentofMicrobiology,ImmunologyandPathology,ColoradoStateUniversity,FortCollins,Colorado,UnitedStatesofAmerica Abstract The development of granulomatous inflammation with caseous necrosis is an important but poorly understood manifestationoftuberculosisinhumansandsomeanimalmodels.Inthisstudywemeasuredthebyproductsofoxidative stressingranulomatouslesionsaswellasthesystemicantioxidantcapacityofBCGvaccinatedandnon-vaccinatedguinea pigsexperimentallyinfectedwithMycobacteriumtuberculosis.Innon-vaccinatedguineapigs,oxidativestresswasevident within2weeksofinfectionasmeasuredbyadecreaseintheserumtotalantioxidantcapacityandbloodglutathionelevels accompaniedbyanincreaseinmalondialdehyde,abyproductoflipidperoxidation,withinlesions.Despiteadecreasein totalandreducedbloodglutathioneconcentrations,therewasanincreaseinlesionglutathionebyimmunohistochemistry inresponsetolocalizedoxidativestress.Inadditiontherewasanincreaseintheexpressionofthehosttranscriptionfactor nuclear erythroid 2 p45-related factor 2 (Nrf2), which regulates several protein and non-proteins antioxidants, including glutathione.DespitetheincreaseincytoplasmicexpressionofNrf2,immunohistochemicalstainingrevealedadefectinNrf2 nucleartranslocationwithingranulomatouslesionsaswellasadecreaseintheexpressionoftheNrf2-regulatedantioxidant protein NQO1. Treating M. tuberculosis–infected guinea pigs with the antioxidant drug N-acetyl cysteine (NAC) partially restoredbloodglutathioneconcentrationsandtheserumtotalantioxidantcapacity.TreatmentwithNACalsodecreased spleenbacterialcounts,aswellasdecreasedthelungandspleenlesionburdenandtheseverityoflesionnecrosis.These datasuggestthattheprogressiveoxidativestressduringexperimentaltuberculosisinguineapigsisdueinparttoadefect inhostantioxidantdefenses,which,weshowhere,canbepartiallyrestoredwithan