Oxygen-Independent Stabilization of Hypoxia Inducible Factor (HIF)-1 during RSV Infection 英文参考文献.docVIP

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Oxygen-Independent Stabilization of Hypoxia Inducible Factor (HIF)-1 during RSV Infection 英文参考文献.doc

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Oxygen-Independent Stabilization of Hypoxia Inducible Factor (HIF)-1 during RSV Infection 英文参考文献

Oxygen-IndependentStabilizationofHypoxiaInducible Factor(HIF)-1duringRSVInfection HeleneA.Haeberle1.,CarinDu¨rrstein1.,PeterRosenberger1,YashodaM.Hosakote3 ,Johannes Kuhlicke1,VolkhardA.J.Kempf2,RobertoP.Garofalo3,HolgerK.Eltzschig1,4* 1DepartmentofAnesthesiologyandIntensiveCareMedicine,UniversityofTu¨bingen,Tu¨bingen,Germany,2MedicalMicrobiologyandHygieneDepartment,Universityof Tu¨bingen, Tu¨bingen, Germany, 3Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America, 4Mucosal Inflammation Program,DepartmentofAnesthesiologyandPerioperativeMedicine,UniversityofColoradoHealthScienceCenter,Denver,Colorado,UnitedStatesofAmerica Abstract Background:Hypoxia-induciblefactor1(HIF)-1aisatranscriptionfactorthatfunctionsasmasterregulatorofmammalian oxygenhomeostasis.Inaddition,recentstudiesidentifiedaroleforHIF-1aastranscriptionalregulatorduringinflammation orinfection.Basedonstudiesshowingthatrespiratorysyncytialvirus(RSV)isamongthemostpotentbiologicalstimulito induceaninflammatorymilieu,wehypothesizedaroleofHIF-1aastranscriptionalregulatorduringinfectionswithRSV. Methodology, Principal Findings: We gained first insight from immunohistocemical studies of RSV-infected human pulmonary epithelia that were stained for HIF-1a. These studies revealed that RSV-positive cells also stained for HIF-1a, suggestingconcomitantHIF-activationduringRSVinfection.Similarly,Westernblotanalysisconfirmedanapproximately8- foldincreaseinHIF-1aprotein24hafterRSVinfection.Incontrast,HIF-1aactivationwasabolishedutilizingUV-treatedRSV. Moreover,HIF-a-regulatedgenes(VEGF,CD73,FN-1,COX-2)wereinducedwithRSVinfectionofwild-typecells.Incontrast, HIF-1a dependent gene induction was abolished in pulmonary epithelia following siRNA mediated repression of HIF-1a. Measurements of the partial pressure of oxygen in the supernatants of RSV infected epithelia or controls revealed no differencesinoxygencontent,suggestingthatHIF-1aactivationisnotcausedbyRSVassociatedhyp