2024
Ezrin drives adaptation of monocytes to the inflamed lung microenvironment
Gudneppanavar R, Di Pietro C, H Öz H, Zhang P, Cheng E, Huang P, Tebaldi T, Biancon G, Halene S, Hoppe A, Kim C, Gonzalez A, Krause D, Egan M, Gupta N, Murray T, Bruscia E. Ezrin drives adaptation of monocytes to the inflamed lung microenvironment. Cell Death & Disease 2024, 15: 864. PMID: 39613751, PMCID: PMC11607083, DOI: 10.1038/s41419-024-07255-8.Peer-Reviewed Original ResearchConceptsActivation of focal adhesion kinaseExtracellular matrixActin-binding proteinsFocal adhesion kinaseLung extracellular matrixKnock-out mouse modelProtein kinase signalingCortical cytoskeletonLoss of ezrinKinase signalingPlasma membraneCell migrationSignaling pathwayEzrinResponse to lipopolysaccharideTissue-resident macrophagesMouse modelLipopolysaccharideCytoskeletonEzrin expressionLung microenvironmentKinaseMonocyte recruitmentProteinAktPrior Influenza Infection Mitigates SARS-CoV-2 Disease in Syrian Hamsters
Di Pietro C, Haberman A, Lindenbach B, Smith P, Bruscia E, Allore H, Vander Wyk B, Tyagi A, Zeiss C. Prior Influenza Infection Mitigates SARS-CoV-2 Disease in Syrian Hamsters. Viruses 2024, 16: 246. PMID: 38400021, PMCID: PMC10891789, DOI: 10.3390/v16020246.Peer-Reviewed Original ResearchConceptsTransient gene expressionSARS-CoV-2Viral replication pathwayReplication pathwayAntiviral pathwaysEndemism patternsUpregulation of innateGene expressionQuantitative RT-PCRMitigated weight lossDual-infected animalsSARS-CoV-2 viral loadSARS-CoV-2 infectionSyrian hamstersSeasonal infection ratesSARS-CoV-2 inoculationLungs of animalsIndividual virusesSARS-CoV-2 diseaseUpper respiratory tractH1N1 infectionRT-PCRBronchoalveolar lavageViral loadCytokine levels
2022
Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis
Öz H, Cheng E, Di Pietro C, Tebaldi T, Biancon G, Zeiss C, Zhang P, Huang P, Esquibies S, Britto C, Schupp J, Murray T, Halene S, Krause D, Egan M, Bruscia E. Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis. Cell Reports 2022, 41: 111797. PMID: 36516754, PMCID: PMC9833830, DOI: 10.1016/j.celrep.2022.111797.Peer-Reviewed Original ResearchConceptsC motif chemokine receptor 2Monocytes/macrophagesLung tissue damageCystic fibrosisTissue damageCF lungPulmonary neutrophilic inflammationPro-inflammatory environmentChemokine receptor 2CF lung diseaseNumber of monocytesSpecific therapeutic agentsGrowth factor βCF transmembrane conductance regulatorLung hyperinflammationLung neutrophiliaNeutrophilic inflammationNeutrophil inflammationInflammation contributesLung damageNeutrophil recruitmentLung diseaseLung tissueReceptor 2Therapeutic targetHuman neutrophil development and functionality are enabled in a humanized mouse model
Zheng Y, Sefik E, Astle J, Karatepe K, Öz HH, Solis AG, Jackson R, Luo HR, Bruscia EM, Halene S, Shan L, Flavell RA. Human neutrophil development and functionality are enabled in a humanized mouse model. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2121077119. PMID: 36269862, PMCID: PMC9618085, DOI: 10.1073/pnas.2121077119.Peer-Reviewed Original ResearchConceptsHumanized mouse modelMouse modelHuman immune systemHuman neutrophilsImmune systemFunctional human immune systemGranulocyte colony-stimulating factorUnique mouse modelColony-stimulating factorHuman G-CSFMISTRG miceG-CSF receptor geneBacterial burdenInfectious challengeG-CSFNeutrophilsMiceNeutrophil developmentReceptor geneDiseaseRecruitment of monocytes primed to express heme oxygenase-1 ameliorates pathological lung inflammation in cystic fibrosis
Di Pietro C, Öz HH, Zhang PX, Cheng EC, Martis V, Bonfield TL, Kelley TJ, Jubin R, Abuchowski A, Krause DS, Egan ME, Murray TS, Bruscia EM. Recruitment of monocytes primed to express heme oxygenase-1 ameliorates pathological lung inflammation in cystic fibrosis. Experimental & Molecular Medicine 2022, 54: 639-652. PMID: 35581352, PMCID: PMC9166813, DOI: 10.1038/s12276-022-00770-8.Peer-Reviewed Original ResearchConceptsHeme oxygenase-1Cystic fibrosisOxygenase-1Myeloid differentiation factor 88Neutrophilic pulmonary inflammationChronic airway infectionDifferentiation factor 88HO-1 levelsDisease mouse modelPseudomonas aeruginosaRecruitment of monocytesResolution of inflammationMonocytes/macrophagesTreatment of CFConditional knockout miceMechanism of actionLung neutrophiliaNeutrophilic inflammationLung inflammationAirway infectionPulmonary diseasePulmonary inflammationFactor 88Lung damageProinflammatory cytokines
2021
Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells
Song Y, Shan L, Gbyli R, Liu W, Strowig T, Patel A, Fu X, Wang X, Xu ML, Gao Y, Qin A, Bruscia EM, Tebaldi T, Biancon G, Mamillapalli P, Urbonas D, Eynon E, Gonzalez DG, Chen J, Krause DS, Alderman J, Halene S, Flavell RA. Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells. Science 2021, 371: 1019-1025. PMID: 33674488, PMCID: PMC8292008, DOI: 10.1126/science.abe2485.Peer-Reviewed Original ResearchConceptsRed blood cellsBlood cellsHuman sickle cell diseaseSickle cell diseaseImmunodeficient murine modelKupffer cell densityBone marrow failureMISTRG miceIntrasplenic injectionSCD pathologyCell diseaseMurine modelComplement C3RBC survivalVivo modelHuman cytokinesPreclinical testingHematopoietic stem cellsHuman red blood cellsMarrow failureFumarylacetoacetate hydrolase geneHuman erythropoiesisHuman liverHuman hepatocytesMice
2019
A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies
Song Y, Rongvaux A, Taylor A, Jiang T, Tebaldi T, Balasubramanian K, Bagale A, Terzi YK, Gbyli R, Wang X, Fu X, Gao Y, Zhao J, Podoltsev N, Xu M, Neparidze N, Wong E, Torres R, Bruscia EM, Kluger Y, Manz MG, Flavell RA, Halene S. A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies. Nature Communications 2019, 10: 366. PMID: 30664659, PMCID: PMC6341122, DOI: 10.1038/s41467-018-08166-x.Peer-Reviewed Original ResearchConceptsPatient-derived xenograftsMyelodysplastic syndromeXenotransplantation modelDysplastic morphologyImmunodeficient murine hostsPre-clinical studiesMDS stem cellsMDS subtypesComprehensive preclinical studiesPreclinical studiesTherapeutic efficacyMurine hostSerial transplantationDrug mechanismsMDS researchStem cell propagationStem cellsDifferentiation potentialHematopoietic stem cell nicheGenetic complexityNovel avenuesStem cell nicheCell propagationDisease representationsImmunodeficient
2018
Surfactant protein C dampens inflammation by decreasing JAK/STAT activation during lung repair
Jin H, Ciechanowicz AK, Kaplan AR, Wang L, Zhang P, Lu YC, Tobin RE, Tobin BA, Cohn L, Zeiss CJ, Lee PJ, Bruscia EM, Krause DS. Surfactant protein C dampens inflammation by decreasing JAK/STAT activation during lung repair. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2018, 314: l882-l892. PMID: 29345196, PMCID: PMC6008135, DOI: 10.1152/ajplung.00418.2017.Peer-Reviewed Original ResearchConceptsAcute respiratory distress syndromeKO miceSurfactant protein CClinical acute respiratory distress syndromeProtein CAlveolar type 2 cellsAnti-inflammatory mediatorsRespiratory distress syndromeBronchoalveolar lavage fluidAnti-inflammatory moleculesPhosphorylated signal transductionType 2 cellsSPC expressionInducible suicide geneJanus kinaseLevels of suppressorDistress syndromeBAL fluidGranulocyte infiltrationJAK1/2 inhibitorLavage fluidProinflammatory phenotypeInflammatory cytokinesSevere inflammationInjury model
2017
Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages
Di Pietro C, Zhang PX, O’Rourke T, Murray TS, Wang L, Britto CJ, Koff JL, Krause DS, Egan ME, Bruscia EM. Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages. Scientific Reports 2017, 7: 10882. PMID: 28883468, PMCID: PMC5589856, DOI: 10.1038/s41598-017-11012-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorCytoskeletal ProteinsDisease Models, AnimalMacrophage ActivationMacrophagesMicePhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktPseudomonas aeruginosaPseudomonas InfectionsSignal TransductionToll-Like Receptor 4ConceptsCystic fibrosis transmembrane conductance regulatorPI3K/AktFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorPI3K/Akt signalingConductance regulatorAnti-bacterial immune responseAkt signalingAltered localizationEzrinCystic fibrosis diseaseMφ activationAktProtein levelsFibrosis diseaseActivationImmune regulationPhagocytosisInductionDirect linkSignalingRegulatorImmune responseMΦMacrophages
2016
Cellular Innate Immunity: An Old Game with New Players
Gasteiger G, D'Osualdo A, Schubert DA, Weber A, Bruscia EM, Hartl D. Cellular Innate Immunity: An Old Game with New Players. Journal Of Innate Immunity 2016, 9: 111-125. PMID: 28006777, PMCID: PMC6738785, DOI: 10.1159/000453397.Peer-Reviewed Original ResearchConceptsInnate immunityMyeloid-derived suppressor cellsInnate lymphoid cellsInnate immune cellsAdaptive immune responsesNovel therapeutic opportunitiesCell typesSuppressor cellsImmune cellsImmune responseLymphoid cellsTherapeutic opportunitiesInfectious diseasesCurrent conceptsMolecular pathwaysImmunityCellsNovel cell typesInflammasomeDiseaseCystic Fibrosis Lung Immunity: The Role of the Macrophage
Bruscia EM, Bonfield TL. Cystic Fibrosis Lung Immunity: The Role of the Macrophage. Journal Of Innate Immunity 2016, 8: 550-563. PMID: 27336915, PMCID: PMC5089923, DOI: 10.1159/000446825.Peer-Reviewed Original ResearchConceptsLung homeostasisCystic fibrosis pathophysiologyTranscriptional shiftMortality of patientsEnvironmental cuesAdaptive immune networkModifier genesMΦ functionMajor morbidityExcessive inflammationMΦ phenotypeLung infectionCF lungCFTR dysfunctionMajor playersHomeostasisDiseaseMacrophagesIntrinsic changesGenesImmune networkPhenotypeMorbidityInflammationPatientsIncreased susceptibility of Cftr−/− mice to LPS-induced lung remodeling
Bruscia E, Zhang P, Barone C, Scholte BJ, Homer R, Krause D, Egan ME. Increased susceptibility of Cftr−/− mice to LPS-induced lung remodeling. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2016, 310: l711-l719. PMID: 26851259, PMCID: PMC4836110, DOI: 10.1152/ajplung.00284.2015.Peer-Reviewed Original ResearchConceptsLung pathologyCF miceImmune responseWT miceChronic inflammationCystic fibrosisAbnormal immune responseChronic pulmonary infectionPersistent immune responseWild-type littermatesCF mouse modelsPseudomonas aeruginosa lipopolysaccharideCF lung pathologyPulmonary infectionChronic administrationLPS exposurePersistent inflammationLung remodelingWT littermatesLung tissueOverall pathologyMouse modelInflammationChronic exposureBacterial products
2015
Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation
Zhang PX, Cheng J, Zou S, D'Souza AD, Koff JL, Lu J, Lee PJ, Krause DS, Egan ME, Bruscia EM. Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation. Nature Communications 2015, 6: 6221. PMID: 25665524, PMCID: PMC4324503, DOI: 10.1038/ncomms7221.Peer-Reviewed Original ResearchConceptsCF macrophagesMiR-199aMicroRNA-199aHyper-inflammatory responseCFTR-deficient miceCystic fibrosis patientsCystic fibrosis lungLung destructionDisease morbidityPharmacological modulationCF miceCF lungFibrosis patientsInnate immunityLungMacrophagesCAV1 expressionDrug celecoxibReduced levelsTLR4CelecoxibMiceCav1PathwayMorbidity
2014
SRF is required for neutrophil migration in response to inflammation
Taylor A, Tang W, Bruscia EM, Zhang PX, Lin A, Gaines P, Wu D, Halene S. SRF is required for neutrophil migration in response to inflammation. Blood 2014, 123: 3027-3036. PMID: 24574460, PMCID: PMC4014845, DOI: 10.1182/blood-2013-06-507582.Peer-Reviewed Original ResearchMeSH KeywordsActin CytoskeletonActinsAnimalsBlotting, WesternCell AdhesionCell MovementChemokinesGene ExpressionInflammationIntegrinsMiceMice, KnockoutMice, TransgenicMicroscopy, ConfocalNeutrophilsN-Formylmethionine Leucyl-PhenylalaninePolymerizationReverse Transcriptase Polymerase Chain ReactionSerum Response FactorSignal TransductionConceptsKO neutrophilsNeutrophil functionNormal neutrophil numbersSerum response factorSites of inflammationRole of SRFLoss of SRFNeutrophil numbersNeutrophil migrationMalignant processNeutrophilsCytokine stimuliChemokine gradientsCell functionExpression levelsIntegrin expression levelsInflammationMicePrimary defenseMegakaryocyte maturationNormal cell functionVivoCellular adhesionMaster regulatorIntegrin activation
2013
Very Small Embryonic‐Like Stem Cells from the Murine Bone Marrow Differentiate into Epithelial Cells of the Lung
Kassmer SH, Jin H, Zhang PX, Bruscia EM, Heydari K, Lee JH, Kim CF, Kassmer SH, Krause DS. Very Small Embryonic‐Like Stem Cells from the Murine Bone Marrow Differentiate into Epithelial Cells of the Lung. Stem Cells 2013, 31: 2759-2766. PMID: 23681901, PMCID: PMC4536826, DOI: 10.1002/stem.1413.Peer-Reviewed Original ResearchConceptsEpithelial cellsSmall embryonic-like stem cellsLung epithelial cellsEmbryonic-like stem cellsStem/progenitor cellsStem cellsDonor miceHematopoietic stem/progenitor cellsBM cellsAdult BMBone marrowSmall embryonicNonhematopoietic cellsProgenitor cellsBroad differentiation potentialVSELsEngraftmentLungHigh rateNumerous reportsAdult stem cellsDifferentiation potentialCellsFirst reportReportReduced Caveolin-1 Promotes Hyperinflammation due to Abnormal Heme Oxygenase-1 Localization in Lipopolysaccharide-Challenged Macrophages with Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator
Zhang PX, Murray TS, Villella VR, Ferrari E, Esposito S, D'Souza A, Raia V, Maiuri L, Krause DS, Egan ME, Bruscia EM. Reduced Caveolin-1 Promotes Hyperinflammation due to Abnormal Heme Oxygenase-1 Localization in Lipopolysaccharide-Challenged Macrophages with Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator. The Journal Of Immunology 2013, 190: 5196-5206. PMID: 23606537, PMCID: PMC3711148, DOI: 10.4049/jimmunol.1201607.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAnimalsCaveolin 1Cells, CulturedChildChild, PreschoolCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorFemaleHeme Oxygenase-1HumansInflammationLipopolysaccharidesLung DiseasesMacrophagesMaleMembrane ProteinsMiceMice, KnockoutNasal PolypsReactive Oxygen SpeciesSignal TransductionToll-Like Receptor 4Young AdultConceptsCav-1 expressionHeme oxygenase-1Dysfunctional cystic fibrosis transmembrane conductance regulatorCystic fibrosis transmembrane conductance regulatorCell surfaceFibrosis transmembrane conductance regulatorProtein caveolin-1Cellular redox statusCell surface localizationCellular oxidative stateTransmembrane conductance regulatorHO-1 enzymePositive feed-forward loopCystic fibrosis macrophagesNegative regulatorCaveolin-1Conductance regulatorCell survivalHO-1 deliverySurface localizationRedox statusMΦ responsesHO-1/CO pathwayPathwayPotential target
2012
Nebulized Hyaluronan Ameliorates lung inflammation in cystic fibrosis mice
Gavina M, Luciani A, Villella VR, Esposito S, Ferrari E, Bressani I, Casale A, Bruscia EM, Maiuri L, Raia V. Nebulized Hyaluronan Ameliorates lung inflammation in cystic fibrosis mice. Pediatric Pulmonology 2012, 48: 761-771. PMID: 22825912, DOI: 10.1002/ppul.22637.Peer-Reviewed Original ResearchConceptsLung inflammationCystic fibrosisLung tissueReactive oxygen speciesScnn1b-Tg miceHuman airway epithelial cellsSaline-treated miceChronic lung inflammationInflammatory protein-2Chronic respiratory diseasesPeroxisome Proliferator-Activated Receptor GammaPotential anti-inflammatory drugsAnti-inflammatory drugsAirway epithelial cellsCystic fibrosis miceIB3-1Myeloperoxidase levelsMIP-2MPO activityMacrophage infiltrationFibrosis miceTumor necrosisExogenous administrationTNFα expressionCF airwaysNonhematopoietic Cells are the Primary Source of Bone Marrow‐Derived Lung Epithelial Cells
Kassmer SH, Bruscia EM, Zhang P, Krause DS. Nonhematopoietic Cells are the Primary Source of Bone Marrow‐Derived Lung Epithelial Cells. Stem Cells 2012, 30: 491-499. PMID: 22162244, PMCID: PMC3725285, DOI: 10.1002/stem.1003.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBacterial ProteinsBone Marrow CellsBone Marrow TransplantationCell SeparationEpithelial CellsGene ExpressionLuminescent ProteinsLungMiceMice, 129 StrainMice, Inbred C57BLMice, KnockoutMicroscopy, ConfocalPulmonary Surfactant-Associated Protein CRecombinant ProteinsSingle-Cell AnalysisConceptsLung epithelial cellsNonhematopoietic cellsBM cellsEpithelial cellsBone marrowLungs of miceType 2 pneumocytesNonhematopoietic stem cellsNonhematopoietic fractionAdult BMPrimitive stem cell populationNull miceProgenitor cellsMiceStem cell populationCell populationsMarrowStem cellsMultiple tissuesHematopoietic stemBMCellsPrevious studiesEngraftmentLung
2011
Abnormal Trafficking and Degradation of TLR4 Underlie the Elevated Inflammatory Response in Cystic Fibrosis
Bruscia EM, Zhang PX, Satoh A, Caputo C, Medzhitov R, Shenoy A, Egan ME, Krause DS. Abnormal Trafficking and Degradation of TLR4 Underlie the Elevated Inflammatory Response in Cystic Fibrosis. The Journal Of Immunology 2011, 186: 6990-6998. PMID: 21593379, PMCID: PMC3111054, DOI: 10.4049/jimmunol.1100396.Peer-Reviewed Original Research
2009
Role for MKL1 in megakaryocytic maturation
Cheng EC, Luo Q, Bruscia EM, Renda MJ, Troy JA, Massaro SA, Tuck D, Schulz V, Mane SM, Berliner N, Sun Y, Morris SW, Qiu C, Krause DS. Role for MKL1 in megakaryocytic maturation. Blood 2009, 113: 2826-2834. PMID: 19136660, PMCID: PMC2661865, DOI: 10.1182/blood-2008-09-180596.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood Cell CountBone MarrowCell DifferentiationCell Line, TumorCells, CulturedDNA-Binding ProteinsGene Expression ProfilingGene Expression RegulationHumansLeukemia, Erythroblastic, AcuteMegakaryocytesMiceMice, Inbred C57BLMice, KnockoutOligonucleotide Array Sequence AnalysisOncogene Proteins, FusionPloidiesRecombinant Fusion ProteinsRNA InterferenceRNA, Small InterferingSerum Response FactorThrombocytopeniaThrombopoiesisThrombopoietinTrans-ActivatorsConceptsMegakaryoblastic leukemia 1Reduced platelet countsSerum response factorMegakaryocytic differentiationPeripheral bloodPlatelet countMKL1 expressionMegakaryoblastic leukemiaBone marrow megakaryocytesMuscle cellsPresence of thrombopoietinPhysiologic maturationHuman erythroleukemia cell lineIncreased numberMarrow megakaryocytesCell linesErythroleukemia cell lineMegakaryocytesMegakaryocytic maturationDifferentiated muscle cellsOverexpressionConcurrent increaseMuscle differentiationCellsMaturation