2023
Future therapies for cystic fibrosis
Allen L, Allen L, Carr S, Davies G, Downey D, Egan M, Forton J, Gray R, Haworth C, Horsley A, Smyth A, Southern K, Davies J. Future therapies for cystic fibrosis. Nature Communications 2023, 14: 693. PMID: 36755044, PMCID: PMC9907205, DOI: 10.1038/s41467-023-36244-2.Peer-Reviewed Original ResearchMeSH KeywordsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorGenetic TherapyHumansMutationConceptsMutation-specific drugsCystic fibrosisSymptom-directed treatmentMultisystem clinical manifestationsCystic fibrosis therapyCystic fibrosis transmembrane conductance regulatorGenetic variantsClinical manifestationsFuture therapiesFibrosis therapyTranslational research collaborationsModulator drugsCFTR modulatorsSingle gene disordersHealth inequalitiesTherapyGene variantsImproved treatmentDrugsPatientsFibrosisFibrosis transmembrane conductance regulatorGene disordersTransmembrane conductance regulatorStrategy group
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 targetNon-Modulator Therapies Developing a Therapy for Every Cystic Fibrosis Patient
Egan M. Non-Modulator Therapies Developing a Therapy for Every Cystic Fibrosis Patient. Clinics In Chest Medicine 2022, 43: 717-725. PMID: 36344076, DOI: 10.1016/j.ccm.2022.06.011.Peer-Reviewed Original ResearchMeSH KeywordsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorGenetic TherapyHumansMutationConceptsModulator therapyCystic fibrosisCystic fibrosis transmembrane conductance regulator (CFTR) modulator therapiesCFTR modulator therapyTreatment of CFCystic fibrosis patientsGenetic-based therapiesMost patientsCF patientsFibrosis patientsTherapyPremature termination codon mutationsTherapeutic agentsPatientsDNA therapyRNA therapyTermination codon mutationsCodon mutationRecruitment 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 ResearchMeSH KeywordsAnimalsCystic FibrosisHeme Oxygenase-1InflammationLipopolysaccharidesLungMiceMonocytesPhosphatidylinositol 3-KinasesPneumoniaConceptsHeme 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 cytokinesSurface conjugation of antibodies improves nanoparticle uptake in bronchial epithelial cells
Luks VL, Mandl H, DiRito J, Barone C, Freedman-Weiss MR, Ricciardi AS, Tietjen GG, Egan ME, Saltzman WM, Stitelman DH. Surface conjugation of antibodies improves nanoparticle uptake in bronchial epithelial cells. PLOS ONE 2022, 17: e0266218. PMID: 35385514, PMCID: PMC8986008, DOI: 10.1371/journal.pone.0266218.Peer-Reviewed Original ResearchConceptsTarget-specific antibodiesNanoparticle uptakeSurface conjugationNanoparticle surface modificationSurface of nanoparticlesCellular uptakeSite-specific geneSpecific cellular bindingNanoparticlesIntracellular deliveryEditing reagentsBronchial epithelial cellsSurface modificationCellular targetingCystic fibrosisTherapeutic agentsEpithelial cellsParticle uptakeFeasible strategyGenetic diseasesFirst demonstrationHuman bronchial epithelial cellsKinetics of antibodiesCellular bindingAppropriate antibodies
2021
SPLUNC1: a novel marker of cystic fibrosis exacerbations
Khanal S, Webster M, Niu N, Zielonka J, Nunez M, Chupp G, Slade MD, Cohn L, Sauler M, Gomez JL, Tarran R, Sharma L, Dela Cruz CS, Egan M, Laguna T, Britto CJ. SPLUNC1: a novel marker of cystic fibrosis exacerbations. European Respiratory Journal 2021, 58: 2000507. PMID: 33958427, PMCID: PMC8571118, DOI: 10.1183/13993003.00507-2020.Peer-Reviewed Original ResearchConceptsAcute pulmonary exacerbationsSPLUNC1 levelsCystic fibrosisClinical outcomesCF participantsLong-term disease controlNasal epithelium clone 1Cystic fibrosis exacerbationsHigher AE riskLung function declineCytokines interleukin-1βTumor necrosis factorAE riskClinical worseningPulmonary exacerbationsStable patientsLung functionAirway clearanceFunction declineSputum collectionAcute inflammationInflammatory cytokinesMicrobiology findingsCF careClinical managementEmerging technologies for cystic fibrosis transmembrane conductance regulator restoration in all people with CF
Egan ME. Emerging technologies for cystic fibrosis transmembrane conductance regulator restoration in all people with CF. Pediatric Pulmonology 2021, 56: s32-s39. PMID: 32681713, PMCID: PMC8114183, DOI: 10.1002/ppul.24965.Peer-Reviewed Original Research
2020
Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis.
Schupp JC, Khanal S, Gomez JL, Sauler M, Adams TS, Chupp GL, Yan X, Poli S, Zhao Y, Montgomery RR, Rosas IO, Dela Cruz CS, Bruscia EM, Egan ME, Kaminski N, Britto CJ. Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2020, 202: 1419-1429. PMID: 32603604, PMCID: PMC7667912, DOI: 10.1164/rccm.202004-0991oc.Peer-Reviewed Original ResearchConceptsCF lung diseaseHealthy control subjectsImmune dysfunctionLung diseaseCystic fibrosisControl subjectsSputum cellsAbnormal chloride transportLung mononuclear phagocytesInnate immune dysfunctionDivergent clinical coursesImmune cell repertoireMonocyte-derived macrophagesCF monocytesAirway inflammationClinical courseProinflammatory featuresCell survival programInflammatory responseTissue injuryCell repertoireImmune functionTranscriptional profilesAlveolar macrophagesMononuclear phagocytesCystic fibrosis transmembrane conductance receptor modulator therapy in cystic fibrosis, an update.
Egan ME. Cystic fibrosis transmembrane conductance receptor modulator therapy in cystic fibrosis, an update. Current Opinion In Pediatrics 2020, 32: 384-388. PMID: 32374578, DOI: 10.1097/mop.0000000000000892.Peer-Reviewed Original ResearchConceptsModulator therapyCystic fibrosisCFTR modulatorsLung functionElexacaftor/tezacaftor/ivacaftorEffective CFTR modulatorsEffective triple therapyTezacaftor/ivacaftorMonths of ageQuality of lifeCystic fibrosis patientsLong-term usePulmonary exacerbationsTriple therapyFirst therapyLong-term benefitsReceptor modulatorsFibrosisFibrosis patientsTherapyUnderlying causeWeight gainPatientsImproved healthCFTR mutationsGlobal chemical effects of the microbiome include new bile-acid conjugations
Quinn RA, Melnik AV, Vrbanac A, Fu T, Patras KA, Christy MP, Bodai Z, Belda-Ferre P, Tripathi A, Chung LK, Downes M, Welch RD, Quinn M, Humphrey G, Panitchpakdi M, Weldon KC, Aksenov A, da Silva R, Avila-Pacheco J, Clish C, Bae S, Mallick H, Franzosa EA, Lloyd-Price J, Bussell R, Thron T, Nelson AT, Wang M, Leszczynski E, Vargas F, Gauglitz JM, Meehan MJ, Gentry E, Arthur TD, Komor AC, Poulsen O, Boland BS, Chang JT, Sandborn WJ, Lim M, Garg N, Lumeng JC, Xavier RJ, Kazmierczak BI, Jain R, Egan M, Rhee KE, Ferguson D, Raffatellu M, Vlamakis H, Haddad GG, Siegel D, Huttenhower C, Mazmanian SK, Evans RM, Nizet V, Knight R, Dorrestein PC. Global chemical effects of the microbiome include new bile-acid conjugations. Nature 2020, 579: 123-129. PMID: 32103176, PMCID: PMC7252668, DOI: 10.1038/s41586-020-2047-9.Peer-Reviewed Original ResearchConceptsChemical interactionChemistryBile acid synthesis genesChemical effectsInflammatory bowel diseaseBile acid conjugatesCompoundsHost bile acidsMolecular familiesBile acid conjugationBowel diseaseGut diseasesMicrobiome dysbiosisConjugationAcidFree miceAmino acid conjugationBile acidsCystic fibrosisX receptorAcid conjugationReduced expressionFurther studiesDiseaseMice
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 responseMΦMacrophagesEffects of Lumacaftor/Ivacaftor in a Pediatric Cohort Homozygous for F508del-CFTR
Egan ME. Effects of Lumacaftor/Ivacaftor in a Pediatric Cohort Homozygous for F508del-CFTR. American Journal Of Respiratory And Critical Care Medicine 2017, 195: 849-850. PMID: 28362199, DOI: 10.1164/rccm.201611-2290ed.Peer-Reviewed Original Research
2016
Increased 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
Genetics of Cystic Fibrosis Clinical Implications
Egan ME. Genetics of Cystic Fibrosis Clinical Implications. Clinics In Chest Medicine 2015, 37: 9-16. PMID: 26857764, DOI: 10.1016/j.ccm.2015.11.002.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulator (CFTR) proteinMutant cystic fibrosis transmembrane conductance regulator (CFTR) proteinRegulator proteinMutational classesModifier genesFunctional consequencesCFTR functionCFTR geneRecessive genetic disorderRespiratory phenotypeGenesSpecific CF genotypesAutosomal recessive genetic disorderGenetic disordersCFTR genotypeCystic fibrosisGenotypesGeneticsProteinCF genotypeMutationsPhenotypeNew therapiesVariantsNanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium
McNeer NA, Anandalingam K, Fields RJ, Caputo C, Kopic S, Gupta A, Quijano E, Polikoff L, Kong Y, Bahal R, Geibel JP, Glazer PM, Saltzman WM, Egan ME. Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium. Nature Communications 2015, 6: 6952. PMID: 25914116, PMCID: PMC4480796, DOI: 10.1038/ncomms7952.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineChloridesCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDNA-Binding ProteinsGenetic TherapyHigh-Throughput Nucleotide SequencingHumansLactic AcidMice, Inbred C57BLNanoparticlesPeptide Nucleic AcidsPolyglycolic AcidPolylactic Acid-Polyglycolic Acid CopolymerPolymersRespiratory MucosaConceptsFacile genome engineeringVivo gene deliveryBiodegradable polymer nanoparticlesTransient gene expressionNanoparticle systemsGene deliveryPolymer nanoparticlesGene correctionGenome engineeringNanoparticlesOff-target effectsPeptide nucleic acidLethal genetic disorderNucleic acidsDonor DNATarget effectsIntranasal deliveryDeliveryCystic fibrosisEngineeringOligonucleotideChloride effluxHuman cellsAirway epitheliumLung tissuePharmacological 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 levelsTLR4CelecoxibMiceCav1PathwayMorbidityAssociation between serum 25‐hydroxyvitamin D level and pulmonary exacerbations in cystic fibrosis
Vanstone MB, Egan ME, Zhang JH, Carpenter TO. Association between serum 25‐hydroxyvitamin D level and pulmonary exacerbations in cystic fibrosis. Pediatric Pulmonology 2015, 50: 441-446. PMID: 25657016, DOI: 10.1002/ppul.23161.Peer-Reviewed Original ResearchConceptsPulmonary function testsCystic fibrosisPulmonary exacerbationsPediatric patientsD levelsYale-New Haven HospitalPediatric CF patientsVitamin D sufficiencyRetrospective chart reviewVitamin D statusStrongest independent determinantCF care centersPatients ages 5Logistic regression analysisAnnual numberD sufficiencyD statusChart reviewClinic visitsLung functionPulmonary functionAntibiotic therapyFunction testsHospitalization ratesIndependent determinants
2014
Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial
Conrad C, Lymp J, Thompson V, Dunn C, Davies Z, Chatfield B, Nichols D, Clancy J, Vender R, Egan M, Quittell L, Michelson P, Antony V, Spahr J, Rubenstein R, Moss R, Herzenberg L, Goss C, Tirouvanziam R. Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. Journal Of Cystic Fibrosis 2014, 14: 219-227. PMID: 25228446, DOI: 10.1016/j.jcf.2014.08.008.Peer-Reviewed Original ResearchConceptsOral N-acetylcysteineLung functionN-acetylcysteineHNE activityHuman neutrophil elastase (HNE) activityDouble-blind proofPlacebo-controlled trialNeutrophil elastase activityPotential of NACLong-term treatmentLung function measuresCystic fibrosis subjectsPlacebo recipientsNeutrophilic inflammationPlacebo groupPulmonary hypertensionClinical outcomesNAC groupCF subjectsCF airwaysSystemic glutathioneNAC recipientsFunction measuresElastase activityInflammation
2013
Reduced 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
Baby bottle steam sterilizers disinfect home nebulizers inoculated with bacterial respiratory pathogens
Towle D, Callan DA, Farrel PA, Egan ME, Murray TS. Baby bottle steam sterilizers disinfect home nebulizers inoculated with bacterial respiratory pathogens. Journal Of Cystic Fibrosis 2012, 12: 512-516. PMID: 23267773, DOI: 10.1016/j.jcf.2012.11.013.Peer-Reviewed Original ResearchConceptsHome nebulizersMethicillin-resistant Staphylococcus aureusBacterial respiratory pathogensResistant Staphylococcus aureusNon-mucoid Pseudomonas aeruginosaMucoid Pseudomonas aeruginosaRespiratory pathogensHaemophilus influenzaeBacterial infectionsClinical settingAdditional studiesBacterial growthStaphylococcus aureusStenotrophomonas maltophiliaPseudomonas aeruginosaViable bacteriaTreatmentNebulizerBurkholderia cepaciaInfectionInfluenzae