Featured Publications
Macrophage migration inhibitory factor deficiency in chronic obstructive pulmonary disease
Sauler M, Leng L, Trentalange M, Haslip M, Shan P, Piecychna M, Zhang Y, Andrews N, Mannam P, Allore H, Fried T, Bucala R, Lee PJ. Macrophage migration inhibitory factor deficiency in chronic obstructive pulmonary disease. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2014, 306: l487-l496. PMID: 24441872, PMCID: PMC3949087, DOI: 10.1152/ajplung.00284.2013.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAge FactorsAgedAged, 80 and overAnimalsApoptosisCellular SenescenceCyclin-Dependent Kinase Inhibitor p16Cyclin-Dependent Kinase Inhibitor p21EmphysemaFemaleHumansIntramolecular OxidoreductasesLungMacrophage Migration-Inhibitory FactorsMaleMiceMice, Inbred C57BLMice, KnockoutMiddle AgedPulmonary Disease, Chronic ObstructiveReceptors, ImmunologicSmokeSmokingTobaccoTumor Suppressor Protein p53Young AdultConceptsChronic obstructive pulmonary diseaseMacrophage migration inhibitory factorPathogenesis of COPDDevelopment of COPDMIF receptor CD74Obstructive pulmonary diseasePulmonary diseaseWT miceReceptor CD74Role of MIFMacrophage migration inhibitory factor deficiencyMigration inhibitory factorNormal alveolar structureMo of ageWild-type controlsMIF concentrationsFormer smokersLung volumePlasma concentrationsSpontaneous emphysemaFactor deficiencyCigarette smokePleiotropic cytokineInhibitory factorAlveolar structuresEndothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury
Sauler M, Zhang Y, Min J, Leng L, Shan P, Roberts S, Jorgensen WL, Bucala R, Lee PJ. Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury. The FASEB Journal 2015, 29: 1940-1949. PMID: 25609432, PMCID: PMC4415022, DOI: 10.1096/fj.14-260299.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorLung endothelial cellsMurine lung endothelial cellsLung injuryEndothelial cellsProtective effectExogenous MIFCD74 deficient miceCD74-dependent mannerHours of hyperoxiaMIF receptor CD74Acute lung injuryHyperoxic lung injuryBronchoalveolar lavage proteinMigration inhibitory factorBronchoalveolar proteinMIF deficiencyMedian survivalEndothelial injuryWT miceAcute oxidative stressReceptor CD74Lavage proteinReceptor antagonistReceptor inhibitorsMicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease
Nouws J, Wan F, Finnemore E, Roque W, Kim SJ, Bazan IS, Li CX, Sköld C, Dai Q, Yan X, Chioccioli M, Neumeister V, Britto CJ, Sweasy J, Bindra RS, Wheelock ÅM, Gomez JL, Kaminski N, Lee PJ, Sauler M. MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease. JCI Insight 2021, 6: e134218. PMID: 33290275, PMCID: PMC7934877, DOI: 10.1172/jci.insight.134218.Peer-Reviewed Original ResearchConceptsCellular stress responseStress responseHomology-directed DNA repairDNA damage responseProtein BRCA1Damage responseCellular stressDNA repairProtein BimCOPD lung tissueLung epithelial cellsCellular responsesExpression arraysEpithelial cell apoptosisDNA damageChronic obstructive pulmonary diseaseBRCA1 expressionCell apoptosisApoptosisEpithelial cellsCritical mechanismMicroRNAsRegulatorObstructive pulmonary diseaseIncreases SusceptibilityCharacterization of the COPD alveolar niche using single-cell RNA sequencing
Sauler M, McDonough JE, Adams TS, Kothapalli N, Barnthaler T, Werder RB, Schupp JC, Nouws J, Robertson MJ, Coarfa C, Yang T, Chioccioli M, Omote N, Cosme C, Poli S, Ayaub EA, Chu SG, Jensen KH, Gomez JL, Britto CJ, Raredon MSB, Niklason LE, Wilson AA, Timshel PN, Kaminski N, Rosas IO. Characterization of the COPD alveolar niche using single-cell RNA sequencing. Nature Communications 2022, 13: 494. PMID: 35078977, PMCID: PMC8789871, DOI: 10.1038/s41467-022-28062-9.Peer-Reviewed Original ResearchConceptsSingle-cell RNA sequencingRNA sequencingCell-specific mechanismsChronic obstructive pulmonary diseaseAdvanced chronic obstructive pulmonary diseaseTranscriptomic network analysisSingle-cell RNA sequencing profilesCellular stress toleranceAberrant cellular metabolismStress toleranceRNA sequencing profilesTranscriptional evidenceCellular metabolismAlveolar nicheSequencing profilesHuman alveolar epithelial cellsChemokine signalingAlveolar epithelial type II cellsObstructive pulmonary diseaseSitu hybridizationType II cellsEpithelial type II cellsSequencingCOPD pathobiologyHuman lung tissue samplesCell Death in the Lung: The Apoptosis–Necroptosis Axis
Sauler M, Bazan IS, Lee PJ. Cell Death in the Lung: The Apoptosis–Necroptosis Axis. Annual Review Of Physiology 2018, 81: 1-28. PMID: 30485762, PMCID: PMC6598441, DOI: 10.1146/annurev-physiol-020518-114320.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsRegulated cell deathCell deathAutophagic cell deathCell death mechanismsSuperfluous cellsAcute respiratory distress syndromeChronic obstructive pulmonary diseasePulmonary arterial hypertensionIdiopathic pulmonary fibrosisObstructive pulmonary diseaseRespiratory distress syndromeDeath mechanismsCellular mechanismsArterial hypertensionDistress syndromePulmonary diseasePulmonary fibrosisPulmonary disordersMajor mechanismDeathNew modalityPathogenesisNecroptosisMechanismApoptosis
2023
Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD
Fan L, McConn K, Plataki M, Kenny S, Williams N, Kim K, Quirke J, Chen Y, Sauler M, Möbius M, Chung K, Gomez E, Choi A, Xu J, Cloonan S. Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD. JCI Insight 2023, 8: e163403. PMID: 37606038, PMCID: PMC10543729, DOI: 10.1172/jci.insight.163403.Peer-Reviewed Original ResearchConceptsChronic obstructive pulmonary diseaseAEC2 cellsFatty acid synthaseCigarette smokeExperimental chronic obstructive pulmonary diseaseBronchoalveolar lavage fluid neutrophilsLipid metabolismDisease-chronic obstructive pulmonary diseaseObstructive pulmonary diseaseAlveolar epithelial type II cellsEpithelial type II cellsType II cellsCOPD developmentPulmonary diseaseAirspace enlargementBALF proteinLipogenesis enzymesFerroptosis markersHigh-throughput lipidomic analysisSurfactant phospholipidsMiceSurfactant synthesisLipid homeostasisII cellsCell functionVISTA (PD-1H) Is a Crucial Immune Regulator to Limit Pulmonary Fibrosis.
Kim S, Adams T, Hu Q, Shin H, Chae G, Lee S, Sharma L, Kwon H, Lee F, Park H, Huh W, Manning E, Kaminski N, Sauler M, Chen L, Song J, Kim T, Kang M. VISTA (PD-1H) Is a Crucial Immune Regulator to Limit Pulmonary Fibrosis. American Journal Of Respiratory Cell And Molecular Biology 2023, 69: 22-33. PMID: 36450109, PMCID: PMC10324045, DOI: 10.1165/rcmb.2022-0219oc.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisPulmonary fibrosisImmune regulatorsTherapeutic potentialHuman idiopathic pulmonary fibrosisCrucial immune regulatorsNovel immune regulatorPulmonary fibrosis micePulmonary fibrosis modelNovel therapeutic targetRole of VISTAWild-type littermatesMonocyte-derived macrophagesT lymphocyte lineageVISTA expressionIPF treatmentAntibody treatmentImmune landscapeFibrotic mediatorsLung fibrosisFibrosis miceInflammatory responseFibrosis modelMyeloid populationsTherapeutic target
2022
A lung targeted miR-29 mimic as a therapy for pulmonary fibrosis
Chioccioli M, Roy S, Newell R, Pestano L, Dickinson B, Rigby K, Herazo-Maya J, Jenkins G, Ian S, Saini G, Johnson SR, Braybrooke R, Yu G, Sauler M, Ahangari F, Ding S, DeIuliis J, Aurelien N, Montgomery RL, Kaminski N. A lung targeted miR-29 mimic as a therapy for pulmonary fibrosis. EBioMedicine 2022, 85: 104304. PMID: 36265417, PMCID: PMC9587275, DOI: 10.1016/j.ebiom.2022.104304.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisNon-human primatesPulmonary fibrosisAnimal modelsPro-fibrotic genesAnti-fibrotic efficacyMiR-29 mimicsHuman peripheral bloodMiR-29b levelsHuman lung fibroblastsIPF patientsIPF diagnosisPeripheral bloodReduced fibrosisAdverse findingsPotential therapyLung slicesTGF-β1Relevant dosesLung fibroblastsNIH-NHLBIFibrosisTherapyCollagen productionProfibrotic gene programMIF is a common genetic determinant of COVID-19 symptomatic infection and severity
Shin JJ, Fan W, Par-Young J, Piecychna M, Leng L, Israni-Winger K, Qing H, Gu J, Zhao H, Schulz WL, Unlu S, Kuster J, Young G, Liu J, Ko AI, Garcia A, Sauler M, Wisnewski AV, Young L, Orduña A, Wang A, Klementina O, Garcia AB, Hegyi P, Armstrong ME, Mitchell P, Ordiz DB, Garami A, Kang I, Bucala R. MIF is a common genetic determinant of COVID-19 symptomatic infection and severity. QJM 2022, 116: 205-212. PMID: 36222594, PMCID: PMC9620729, DOI: 10.1093/qjmed/hcac234.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorLow-expression MIF alleleCOVID-19 infectionMIF allelesCATT7 alleleHealthy controlsCOVID-19Serum macrophage migration inhibitory factorSymptomatic SARS-CoV-2 infectionHigher serum MIF levelsHigh-expression MIF allelesRetrospective case-control studySARS-CoV-2 infectionFunctional polymorphismsAvailable clinical characteristicsMultinational retrospective studySerum MIF levelsUninfected healthy controlsSymptomatic COVID-19Tertiary medical centerHealthy control subjectsCase-control studyMigration inhibitory factorCoronavirus disease 2019Common functional polymorphismsEpidermal Growth Factor Receptor Inhibition Is Protective in Hyperoxia‐Induced Lung Injury
Harris ZM, Sun Y, Joerns J, Clark B, Hu B, Korde A, Sharma L, Shin HJ, Manning EP, Placek L, Unutmaz D, Stanley G, Chun H, Sauler M, Rajagopalan G, Zhang X, Kang MJ, Koff JL. Epidermal Growth Factor Receptor Inhibition Is Protective in Hyperoxia‐Induced Lung Injury. Oxidative Medicine And Cellular Longevity 2022, 2022: 9518592. PMID: 36193076, PMCID: PMC9526641, DOI: 10.1155/2022/9518592.Peer-Reviewed Original ResearchConceptsAcute lung injuryEpidermal growth factor receptorAlveolar epithelial cellsLung injurySevere hyperoxiaEGFR inhibitionEpithelial cellsHyperoxia-Induced Lung InjuryRole of EGFRMurine alveolar epithelial cellsGrowth factor receptor inhibitionWorse clinical outcomesEpidermal growth factor receptor inhibitionHuman alveolar epithelial cellsWild-type littermatesPoly (ADP-ribose) polymeraseTerminal dUTP nickGrowth factor receptorClinical outcomesImproved survivalReceptor inhibitionLung repairProtective roleComplex roleEGFR deletionCompromised Cardiopulmonary Function in Fibulin-5 Deficient Mice.
Ramachandra AB, Mikush N, Sauler M, Humphrey JD, Manning EP. Compromised Cardiopulmonary Function in Fibulin-5 Deficient Mice. Journal Of Biomechanical Engineering 2022, 144 PMID: 35171214, PMCID: PMC8990734, DOI: 10.1115/1.4053873.Peer-Reviewed Original ResearchConceptsRight heart functionDeficient micePulmonary arteryHeart functionCompromised right ventricular functionFibulin-5 deficient micePulmonary arterial structureRight ventricular functionVentilation-perfusion relationshipsElastic fiber contentElastic fibersFiber dysfunctionLung compliancePulmonary healthVentricular functionCardiopulmonary functionAlveolar disruptionPulmonary pathologyLung parenchymaMurine modelMouse modelArterial structureHistological quantificationElastic laminaRight circulationSex differences and altered mitophagy in experimental pulmonary hypertension
Bazan IS, Kim SJ, Ardito TA, Zhang Y, Shan P, Sauler M, Lee P. Sex differences and altered mitophagy in experimental pulmonary hypertension. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2022, 322: l761-l769. PMID: 35137625, PMCID: PMC9076415, DOI: 10.1152/ajplung.00019.2020.Peer-Reviewed Original ResearchConceptsPulmonary hypertensionPathogenesis of PHFemale-predominant diseaseRight heart failurePulmonary arterial pressureExperimental pulmonary hypertensionMitochondrial dysfunctionLung endothelial cellsSex differencesMouse lung endothelial cellsInhibition of ParkinArterial pressureHeart failurePulmonary arteryMitochondrial respiratory capacityPoor outcomeHigh prevalenceSevere diseaseAnimal modelsEndothelial cellsParkin expressionOxidative stressCell proliferationHypertensionSex
2021
MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model
Tilstam PV, Schulte W, Holowka T, Kim BS, Nouws J, Sauler M, Piecychna M, Pantouris G, Lolis E, Leng L, Bernhagen J, Fingerle-Rowson G, Bucala R. MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model. Journal Of Clinical Investigation 2021, 131: e127171. PMID: 34850744, PMCID: PMC8631602, DOI: 10.1172/jci127171.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCytokinesDisease Models, AnimalFemaleFlow CytometryGene Expression ProfilingInflammationIntramolecular OxidoreductasesLeukocyte CountMacrophage Migration-Inhibitory FactorsMacrophagesMacrophages, PeritonealMaleMiceMice, Inbred C57BLMice, TransgenicPeritoneal LavagePhenotypeProtein BindingRNA-SeqSepsisSignal TransductionConceptsMacrophage migration inhibitory factorSmall peritoneal macrophagesLarge peritoneal macrophagesPolymicrobial sepsisPeritoneal macrophagesMIF receptor CD74MIF promoter polymorphismsMIF-2Migration inhibitory factorPolymicrobial sepsis modelMIF deficiencyAdoptive transferSeptic shockSurvival benefitInfectious insultsMIF antibodyExcessive inflammationInflammatory cytokinesReceptor CD74Sepsis modelProtective effectPeritoneal cavityDifferent infectionsPromoter polymorphismInflammatory macrophagesMetformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment.
Polverino F, Wu TD, Rojas-Quintero J, Wang X, Mayo J, Tomchaney M, Tram J, Packard S, Zhang D, Cleveland KH, Cordoba-Lanus E, Owen CA, Fawzy A, Kinney GL, Hersh CP, Hansel NN, Doubleday K, Sauler M, Tesfaigzi Y, Ledford JG, Casanova C, Zmijewski J, Konhilas J, Langlais PR, Schnellmann R, Rahman I, McCormack M, Celli B. Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment. American Journal Of Respiratory And Critical Care Medicine 2021, 204: 651-666. PMID: 34033525, PMCID: PMC8521702, DOI: 10.1164/rccm.202012-4510oc.Peer-Reviewed Original ResearchConceptsChronic obstructive pulmonary diseaseMetformin useEmphysema progressionEmphysematous chronic obstructive pulmonary diseaseOxidative stressSmall airway remodelingProtective actionEfficacy of metforminObstructive pulmonary diseaseCigarette smoke inhalationPercentage of emphysemaER stressEndoplasmic reticulum stressEmphysema treatmentAirway remodelingPulmonary diseasePulmonary inflammationAirspace enlargementClinical evidenceLung agingAge-related diseasesSmoke inhalationClinical trialsMuscle injuryMetformin effectsMacrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension
Ntokou A, Dave JM, Kauffman AC, Sauler M, Ryu C, Hwa J, Herzog EL, Singh I, Saltzman WM, Greif DM. Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension. JCI Insight 2021, 6: e139067. PMID: 33591958, PMCID: PMC8026182, DOI: 10.1172/jci.insight.139067.Peer-Reviewed Original ResearchConceptsRight ventricle hypertrophyPulmonary hypertensionDistal muscularizationSmooth muscle cellsHypoxia-inducible factor 2APulmonary arterial hypertension patientsLysM-Cre miceArterial hypertension patientsHuman pulmonary hypertensionHypoxia-inducible factor 1aPlatelet-derived growth factorMacrophage-conditioned mediumVentricle hypertrophyHypertension patientsDistal arteriolesMacrophage accumulationFl miceCardiovascular diseaseInterventional strategiesMuscularizationHypoxia exposureExcess macrophagesSMC proliferationLethal diseaseMuscle cells
2020
Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF‐2 in adipose tissue during endotoxemia
Kim B, Tilstam PV, Arnke K, Leng L, Ruhl T, Piecychna M, Schulte W, Sauler M, Frueh FS, Storti G, Lindenblatt N, Giovanoli P, Pallua N, Bernhagen J, Bucala R. Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF‐2 in adipose tissue during endotoxemia. The FASEB Journal 2020, 34: 4219-4233. PMID: 31961019, PMCID: PMC7060131, DOI: 10.1096/fj.201901511r.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorWhite adipose tissueAdipose tissue macrophagesAdipose tissueElevated macrophage migration inhibitory factorInflammatory cytokine macrophage migration inhibitory factorVisceral white adipose tissueCytokine macrophage migration inhibitory factorPro-inflammatory macrophage polarizationMIF family proteinsPro-inflammatory phenotypeAnti-inflammatory phenotypeMIF-2Migration inhibitory factorWild-type miceHuman adipose tissueMurine endotoxemia modelMIF cytokineMIF deficiencySystemic inflammationDifferential regulationHealthy patientsEndotoxemia modelPeritoneal fluidLeading cause
2019
Endothelial toll‐like receptor 4 maintains lung integrity via epigenetic suppression of p16INK4a
Kim S, Shan P, Hwangbo C, Zhang Y, Min J, Zhang X, Ardito T, Li A, Peng T, Sauler M, Lee PJ. Endothelial toll‐like receptor 4 maintains lung integrity via epigenetic suppression of p16INK4a. Aging Cell 2019, 18: e12914. PMID: 30790400, PMCID: PMC6516428, DOI: 10.1111/acel.12914.Peer-Reviewed Original ResearchConceptsToll-like receptor 4Senescence-related gene expressionLung integritySenescence-associated genesReceptor 4New functional roleLung ECsInnate immune receptor toll-like receptor 4Immune receptor toll-like receptor 4Role of TLR4Endothelial Toll-like receptor 4Receptor Toll-like receptor 4Epigenetic regulationHistone H4Epigenetic suppressionTLR4-/- miceGene expressionEndogenous p16Molecular mechanismsWild-type miceNovel roleExpression of p16Lung endothelial cellsFunctional roleDistinct roles
2018
BPIFA1 regulates lung neutrophil recruitment and interferon signaling during acute inflammation
Britto CJ, Niu N, Khanal S, Huleihel L, Herazo-Maya J, Thompson A, Sauler M, Slade MD, Sharma L, Dela Cruz CS, Kaminski N, Cohn LE. BPIFA1 regulates lung neutrophil recruitment and interferon signaling during acute inflammation. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2018, 316: l321-l333. PMID: 30461288, PMCID: PMC6397348, DOI: 10.1152/ajplung.00056.2018.Peer-Reviewed Original ResearchConceptsLung inflammationAcute inflammationC motif chemokine ligand 10Lung neutrophil recruitmentRegulation of CXCL10Acute lung inflammationBronchoalveolar lavage concentrationsChemokine ligand 10Innate immune responseIFN regulatory factorIntranasal LPSLavage concentrationsLung recruitmentNeutrophil recruitmentWT miceImmune effectsLung diseasePMN recruitmentInflammatory responseLPS treatmentLung tissueInflammatory signalsImmune responseImmunomodulatory propertiesInflammationEndothelial cell‐secreted MIF reduces pericyte contractility and enhances neutrophil extravasation
Pellowe AS, Sauler M, Hou Y, Merola J, Liu R, Calderon B, Lauridsen HM, Harris MR, Leng L, Zhang Y, Tilstam PV, Pober JS, Bucala R, Lee PJ, Gonzalez AL. Endothelial cell‐secreted MIF reduces pericyte contractility and enhances neutrophil extravasation. The FASEB Journal 2018, 33: 2171-2186. PMID: 30252532, PMCID: PMC6338650, DOI: 10.1096/fj.201800480r.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorNeutrophil transmigrationNeutrophil extravasationPericyte contractilitySelective deletionMIF knockout miceAcute lung injuryMigration inhibitory factorHuman neutrophil transmigrationMyosin light chain phosphorylationLung injuryNeutrophil infiltrationBronchoalveolar lavageInflammatory disordersKnockout miceInhibitory factorMicro-ELISAContractilityLight chain phosphorylationPhosphorylated myosin light chainEndothelial cellsBarrier functionExtravasationPericytesParacrine signals
2016
MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis
Yoo SA, Leng L, Kim BJ, Du X, Tilstam PV, Kim KH, Kong JS, Yoon HJ, Liu A, Wang T, Song Y, Sauler M, Bernhagen J, Ritchlin CT, Lee P, Cho CS, Kim WU, Bucala R. MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: e7917-e7926. PMID: 27872288, PMCID: PMC5150393, DOI: 10.1073/pnas.1612717113.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorHigh-expression MIF allelesJoint destructionRheumatoid arthritisMIF allelesProgressive joint destructionInvasive phenotypeFibroblast-like synoviocytesMigration inhibitory factorJoint erosionsMIF receptorAutoimmune responseMIF pathwaySynovial fibroblastsCell surface CD74Autocrine pathwayCD44 expressionInhibitory factorPharmacologic inhibitionTumor invasionArthritisInvasive propertiesCD44 receptorCD44Receptor complex