2024
Noninvasive assessment of the lung inflammation-fibrosis axis by targeted imaging of CMKLR1
Mannes P, Adams T, Farsijani S, Barnes C, Latoche J, Day K, Nedrow J, Ahangari F, Kaminski N, Lee J, Tavakoli S. Noninvasive assessment of the lung inflammation-fibrosis axis by targeted imaging of CMKLR1. Science Advances 2024, 10: eadm9817. PMID: 38896611, PMCID: PMC11186491, DOI: 10.1126/sciadv.adm9817.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisFibrotic lung diseaseRisk stratificationMurine modelLung fibrosisLung diseaseModel of bleomycin-induced lung fibrosisBleomycin-induced lung fibrosisImaging biomarkersMurine model of bleomycin-induced lung fibrosisBronchoalveolar lavage cellsMonocyte-derived macrophagesPositron emission tomographyInflammatory endotypesPulmonary fibrosisLavage cellsPoor survivalNoninvasive assessmentTherapeutic monitoringEmission tomographyCMKLR1FibrosisClinical trajectoryLungLung regions
2023
microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis
Ahangari F, Price N, Malik S, Chioccioli M, Bärnthaler T, Adams T, Kim J, Pradeep S, Ding S, Cosme C, Rose K, McDonough J, Aurelien N, Ibarra G, Omote N, Schupp J, DeIuliis G, Nunez J, Sharma L, Ryu C, Dela Cruz C, Liu X, Prasse A, Rosas I, Bahal R, Fernandez-Hernando C, Kaminski N. microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis. JCI Insight 2023, 8: e158100. PMID: 36626225, PMCID: PMC9977502, DOI: 10.1172/jci.insight.158100.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisPulmonary fibrosisMiR-33MiR-33 levelsSpecific genetic ablationBronchoalveolar lavage cellsNovel therapeutic approachesMitochondrial homeostasisFatty acid metabolismMacrophages protectsBleomycin injuryLavage cellsLung fibrosisHealthy controlsInflammatory responseTherapeutic approachesImmunometabolic responsesCholesterol effluxFibrosisFatal diseasePharmacological inhibitionSterol regulatory element-binding protein (SREBP) genesGenetic ablationMacrophagesEx vivo mouse
2022
Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis.
Ahangari F, Becker C, Foster DG, Chioccioli M, Nelson M, Beke K, Wang X, Justet A, Adams T, Readhead B, Meador C, Correll K, Lili LN, Roybal HM, Rose KA, Ding S, Barnthaler T, Briones N, DeIuliis G, Schupp JC, Li Q, Omote N, Aschner Y, Sharma L, Kopf KW, Magnusson B, Hicks R, Backmark A, Dela Cruz CS, Rosas I, Cousens LP, Dudley JT, Kaminski N, Downey GP. Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2022, 206: 1463-1479. PMID: 35998281, PMCID: PMC9757097, DOI: 10.1164/rccm.202010-3832oc.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisHuman precision-cut lung slicesPrecision-cut lung slicesPulmonary fibrosisNormal human lung fibroblastsEpithelial-mesenchymal transitionHuman lung fibroblastsFibrogenic pathwaysPreclinical modelsMurine modelLung slicesSrc kinase inhibitorLung fibroblastsKinase inhibitorsAmelioration of fibrosisSelective Src kinase inhibitorHuman lung fibrosisWhole lung extractsPotential therapeutic efficacyIPF diseaseIPF treatmentLung functionInflammatory cascadeLung fibrosisAntifibrotic efficacyA 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 program
2020
Retrograde signaling by a mtDNA-encoded non-coding RNA preserves mitochondrial bioenergetics
Blumental-Perry A, Jobava R, Bederman I, Degar A, Kenche H, Guan B, Pandit K, Perry N, Molyneaux N, Wu J, Prendergas E, Ye Z, Zhang J, Nelson C, Ahangari F, Krokowski D, Guttentag S, Linden P, Townsend D, Miron A, Kang M, Kaminski N, Perry Y, Hatzoglou M. Retrograde signaling by a mtDNA-encoded non-coding RNA preserves mitochondrial bioenergetics. Communications Biology 2020, 3: 626. PMID: 33127975, PMCID: PMC7603330, DOI: 10.1038/s42003-020-01322-4.Peer-Reviewed Original ResearchConceptsMitochondrial genomeNuclear-encoded genesCell type-specific mannerNon-coding RNASteady-state transcriptionMitochondrial energy metabolismControl regionPositive regulationMitochondrial bioenergeticsMitochondria stressMitochondrial functionSpecific mannerAlveolar epithelial type II cellsEnergy metabolismType II cellsEpithelial type II cellsGenomePhysiological stressRNAII cellsCellsMouse lungTranscriptionGenesMitochondriaAn endothelial microRNA-1–regulated network controls eosinophil trafficking in asthma and chronic rhinosinusitis
Korde A, Ahangari F, Haslip M, Zhang X, Liu Q, Cohn L, Gomez JL, Chupp G, Pober JS, Gonzalez A, Takyar SS. An endothelial microRNA-1–regulated network controls eosinophil trafficking in asthma and chronic rhinosinusitis. Journal Of Allergy And Clinical Immunology 2020, 145: 550-562. PMID: 32035607, PMCID: PMC8440091, DOI: 10.1016/j.jaci.2019.10.031.Peer-Reviewed Original ResearchConceptsMiR-1 levelsAllergic airway inflammationChronic rhinosinusitisP-selectin levelsEndothelium-specific overexpressionLung endotheliumAirway eosinophiliaAirway inflammationAsthmatic patientsTissue eosinophiliaMiR-1House dust mite modelEndothelial cellsThymic stromal lymphopoietinNumber of hospitalizationsHuman lung endotheliumIL-13 stimulationCRS cohortQuantitative RT-PCRSputum eosinophiliaAirway obstructionAsthma modelAsthma phenotypesLentiviral vector deliveryMurine model
2019
Transcriptional regulatory model of fibrosis progression in the human lung
McDonough JE, Ahangari F, Li Q, Jain S, Verleden SE, Herazo-Maya J, Vukmirovic M, DeIuliis G, Tzouvelekis A, Tanabe N, Chu F, Yan X, Verschakelen J, Homer RJ, Manatakis DV, Zhang J, Ding J, Maes K, De Sadeleer L, Vos R, Neyrinck A, Benos PV, Bar-Joseph Z, Tantin D, Hogg JC, Vanaudenaerde BM, Wuyts WA, Kaminski N. Transcriptional regulatory model of fibrosis progression in the human lung. JCI Insight 2019, 4 PMID: 31600171, PMCID: PMC6948862, DOI: 10.1172/jci.insight.131597.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisAdvanced fibrosisAlveolar surface densityFibrosis progressionLung fibrosisHuman lungDynamic Regulatory Events MinerExtent of fibrosisIPF lungsPulmonary fibrosisControl lungsIPF tissueB lymphocytesFibrosisLungLinear mixed-effects modelsMixed-effects modelsGene expression changesSystems biology modelsDifferential gene expression analysisGene expression analysisProgressionGene expression networksRNA sequencingBiology modelsRole of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis
Xylourgidis N, Min K, Ahangari F, Yu G, Herazo-Maya JD, Karampitsakos T, Aidinis V, Binzenhöfer L, Bouros D, Bennett AM, Kaminski N, Tzouvelekis A. Role of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2019, 317: l678-l689. PMID: 31483681, PMCID: PMC6879900, DOI: 10.1152/ajplung.00264.2018.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibiotics, AntineoplasticBleomycinDual-Specificity PhosphatasesFemaleFibroblastsHumansMAP Kinase Signaling SystemMiceMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein Kinase PhosphatasesPhosphorylationPulmonary FibrosisSignal TransductionTransforming Growth Factor beta1ConceptsPulmonary fibrosisLung fibrosisFibrogenic genesLung fibroblastsM1 macrophage phenotypeIdiopathic pulmonary fibrosisHuman lung fibrosisGrowth factor-β1Levels of hydroxyprolineProtein kinase phosphatase 5IPF lungsReduced fibrosisMuscle fibrosisProfibrogenic effectsTGF-β1Smad7 levelsTherapeutic targetAnimal modelsFactor-β1FibrosisSmad3 phosphorylationEnhanced p38 MAPK activityP38 MAPK activityMyofibroblast differentiationMKP-5 expressionIntegrating multiomics longitudinal data to reconstruct networks underlying lung development
Ding J, Ahangari F, Espinoza CR, Chhabra D, Nicola T, Yan X, Lal CV, Hagood JS, Kaminski N, Bar-Joseph Z, Ambalavanan N. Integrating multiomics longitudinal data to reconstruct networks underlying lung development. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2019, 317: l556-l568. PMID: 31432713, PMCID: PMC6879899, DOI: 10.1152/ajplung.00554.2018.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornChildChild, PreschoolDNA MethylationEpigenesis, GeneticFemaleGene Expression ProfilingGene Expression Regulation, DevelopmentalGene Regulatory NetworksHigh-Throughput Nucleotide SequencingHumansImmunity, InnateInfantInfant, NewbornLungMaleMiceMice, Inbred C57BLMicroRNAsOrganogenesisProteomicsPulmonary AlveoliRNA, MessengerSingle-Cell AnalysisTranscriptomeConceptsSingle-cell RNA-seq dataLung developmentDynamic regulatory networksOmics data setsRNA-seq dataIndividual cell typesHuman lung developmentRegulatory networksDNA methylationLaser capture microdissectionEpigenetic changesExpression trajectoriesKey pathwaysCell typesActive pathwaysCapture microdissectionRegulatorKey eventsInnate immunityNew insightsSpecific key eventsPathwayComprehensive understandingProteomicsMethylation
2017
Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function
Yu G, Tzouvelekis A, Wang R, Herazo-Maya JD, Ibarra GH, Srivastava A, de Castro JPW, DeIuliis G, Ahangari F, Woolard T, Aurelien N, Arrojo e Drigo R, Gan Y, Graham M, Liu X, Homer RJ, Scanlan TS, Mannam P, Lee PJ, Herzog EL, Bianco AC, Kaminski N. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nature Medicine 2017, 24: 39-49. PMID: 29200204, PMCID: PMC5760280, DOI: 10.1038/nm.4447.Peer-Reviewed Original Research
2016
SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis
Tzouvelekis A, Yu G, Lino Cardenas CL, Herazo-Maya JD, Wang R, Woolard T, Zhang Y, Sakamoto K, Lee H, Yi JS, DeIuliis G, Xylourgidis N, Ahangari F, Lee PJ, Aidinis V, Herzog EL, Homer R, Bennett AM, Kaminski N. SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2016, 195: 500-514. PMID: 27736153, PMCID: PMC5378419, DOI: 10.1164/rccm.201602-0329oc.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisPulmonary fibrosisProfibrotic stimuliLung fibroblastsChronic fatal lung diseaseMyofibroblast differentiationPrimary human lung fibroblastsFatal lung diseaseNovel therapeutic strategiesVivo therapeutic effectPotential therapeutic usefulnessHuman lung fibroblastsMouse lung fibroblastsDismal prognosisFibroblastic fociLung fibrosisLung diseaseBleomycin modelTherapeutic effectTherapeutic usefulnessTherapeutic strategiesTherapeutic targetTransgenic miceFibrosisSHP2 overexpression
2015
Chitinase 3–like-1 Regulates Both Visceral Fat Accumulation and Asthma-like Th2 Inflammation
Ahangari F, Sood A, Ma B, Takyar S, Schuyler M, Qualls C, Dela Cruz CS, Chupp GL, Lee CG, Elias JA. Chitinase 3–like-1 Regulates Both Visceral Fat Accumulation and Asthma-like Th2 Inflammation. American Journal Of Respiratory And Critical Care Medicine 2015, 191: 746-757. PMID: 25629580, PMCID: PMC4407482, DOI: 10.1164/rccm.201405-0796oc.Peer-Reviewed Original ResearchConceptsHigh-fat dietTh2 inflammationTh2 responsesFat accumulationChitinase 3Genesis of obesityRole of CHI3L1Lower lung functionLean control subjectsVisceral fat accumulationPathogenesis of asthmaWhite adipose tissue accumulationAdipose tissue accumulationCase-control studySerum CHI3L1Truncal adiposityWAT accumulationPersistent asthmaTruncal obesityLung functionObese subjectsVisceral fatAsthma incidenceControl subjectsRisk factors
2013
VEGF controls lung Th2 inflammation via the miR-1–Mpl (myeloproliferative leukemia virus oncogene)–P-selectin axis
Takyar S, Vasavada H, Zhang JG, Ahangari F, Niu N, Liu Q, Lee CG, Cohn L, Elias JA. VEGF controls lung Th2 inflammation via the miR-1–Mpl (myeloproliferative leukemia virus oncogene)–P-selectin axis. Journal Of Experimental Medicine 2013, 210: 1993-2010. PMID: 24043765, PMCID: PMC3782056, DOI: 10.1084/jem.20121200.Peer-Reviewed Original ResearchConceptsVascular endothelial growth factorTh2 inflammationLung endotheliumMiR-1Th2-mediated lung inflammationIL-13 overexpressionLung-specific overexpressionHouse dust mitePotential therapeutic targetEndothelial growth factorMiR-1 expressionLung inflammationInflammatory disordersDust miteInflammation modelInflammatory responseIntranasal deliveryRole of microRNAsTherapeutic targetInflammationP-selectinGrowth factorVivo knockdownEffector pathwaysEndotheliumChitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2
He CH, Lee CG, Dela Cruz CS, Lee CM, Zhou Y, Ahangari F, Ma B, Herzog EL, Rosenberg SA, Li Y, Nour AM, Parikh CR, Schmidt I, Modis Y, Cantley L, Elias JA. Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2. Cell Reports 2013, 4: 830-841. PMID: 23972995, PMCID: PMC3988532, DOI: 10.1016/j.celrep.2013.07.032.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisChitinase-3-Like Protein 1GlycoproteinsHumansInflammasomesInterleukin-13Interleukin-13 Receptor alpha2 SubunitLung NeoplasmsMacrophagesMAP Kinase Signaling SystemMelanomaMiceMice, Inbred C57BLOxidative StressProtein BindingTransforming Growth Factor betaWnt Signaling PathwayConceptsProtein kinase B/AktWnt/β-catenin signalingΒ-catenin signalingCritical roleGene familyMultimeric complexesProtein kinaseMacrophage mitogenDisease toleranceCell deathAntibacterial responseReceptor α2Antipathogen responsesChitinase 3IL-13Rα2IL-13 receptor α2Inflammasome activationBacterial killingKinaseOxidant injuryReceptorsMelanoma metastasesCHI3L1SignalingAkt
2012
Chitinase 1 Is a Biomarker for and Therapeutic Target in Scleroderma-Associated Interstitial Lung Disease That Augments TGF-β1 Signaling
Lee CG, Herzog EL, Ahangari F, Zhou Y, Gulati M, Lee CM, Peng X, Feghali-Bostwick C, Jimenez SA, Varga J, Elias JA. Chitinase 1 Is a Biomarker for and Therapeutic Target in Scleroderma-Associated Interstitial Lung Disease That Augments TGF-β1 Signaling. The Journal Of Immunology 2012, 189: 2635-2644. PMID: 22826322, PMCID: PMC4336775, DOI: 10.4049/jimmunol.1201115.Peer-Reviewed Original ResearchConceptsInterstitial lung diseaseTGF-β1 signalingPulmonary fibrosisLung diseaseTherapeutic targetScleroderma-Associated Interstitial Lung DiseaseDifferent patient cohortsTGF-β receptor 1Wild-type miceTGF-β1 effectsSSc-ILDLung involvementSSc patientsSystemic sclerosisPulmonary responseLung fibrosisPoor prognosisCHIT1 activityPatient cohortPathogenetic mechanismsReceptor expressionMurine modelingTGF-β1Disease severityPotential biomarkersChitinase-like Proteins in Lung Injury, Repair, and Metastasis
Lee CG, Dela Cruz CS, Ma B, Ahangari F, Zhou Y, Halaban R, Sznol M, Elias JA. Chitinase-like Proteins in Lung Injury, Repair, and Metastasis. Annals Of The American Thoracic Society 2012, 9: 57-61. PMID: 22550243, PMCID: PMC3359113, DOI: 10.1513/pats.201112-056ms.Peer-Reviewed Original Research
2011
Studies of Vascular Endothelial Growth Factor in Asthma and Chronic Obstructive Pulmonary Disease
Lee CG, Ma B, Takyar S, Ahangari F, DelaCruz C, He CH, Elias JA. Studies of Vascular Endothelial Growth Factor in Asthma and Chronic Obstructive Pulmonary Disease. Annals Of The American Thoracic Society 2011, 8: 512-515. PMID: 22052929, PMCID: PMC3359071, DOI: 10.1513/pats.201102-018mw.Peer-Reviewed Original ResearchConceptsVascular endothelial growth factorRIG-like helicaseTh2 inflammationEndothelial growth factorImmune pathwaysVirus-induced COPD exacerbationsChronic obstructive pulmonary diseaseViral pathogen-associated molecular patternsRole of VEGFGrowth factorDendritic cell activationObstructive pulmonary diseaseAbrogation of VEGFInnate immune pathwaysUseful therapeutic strategyVEGF receptor blockadePathogen-associated molecular patternsTissue responseCOPD exacerbationsMucus metaplasiaEosinophilic inflammationReceptor blockadePulmonary diseaseSubepithelial fibrosisCytokine elaborationRole of Chitin and Chitinase/Chitinase-Like Proteins in Inflammation, Tissue Remodeling, and Injury
Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ, He CH, Takyar S, Elias JA. Role of Chitin and Chitinase/Chitinase-Like Proteins in Inflammation, Tissue Remodeling, and Injury. Annual Review Of Physiology 2011, 73: 479-501. PMID: 21054166, PMCID: PMC3864643, DOI: 10.1146/annurev-physiol-012110-142250.Peer-Reviewed Original ResearchConceptsBRP-39/YKLAdaptive Th2 immunityTissue remodelingChitinase-like proteinsAlternative macrophage activationTh2 inflammationInnate inflammationLung injuryTh2 immunityAcidic mammalian chitinaseAncient gene familyIL-13YKL-40Tissue injuryNumber of chitinasesEffector functionsMacrophage activationFamily of chitinasesInflammationDisease severityInjuryRole of chitinMammalian chitinaseGene familyEndogenous chitin
2002
Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer
Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, Ramsay J, McKinnon PJ, Swift M, Lavin MF. Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nature Genetics 2002, 32: 185-190. PMID: 12195425, DOI: 10.1038/ng958.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtaxia TelangiectasiaAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsCell SurvivalChromosomesDNA-Binding ProteinsFemaleGamma RaysGenetic Predisposition to DiseaseHeterozygoteHumansMaleMiceMice, Inbred C57BLMutation, MissenseNeoplasmsPenetranceProtein Serine-Threonine KinasesTumor Suppressor ProteinsConceptsAtaxia telangiectasiaATM kinase activityDominant negative effectATM cDNAGenome instabilityHeterozygous miceRadiation-induced chromosomal aberrationsKinase activityCancer predispositionFrame deletionMutationsControl cellsGenesChromosomal aberrationsCellsCDNAMouse carriersDeletionMiceHeterozygous carriersAtmFirst timeExpressionFurther support
2001
Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype.
Spring K, Cross S, Li C, Watters D, Ben-Senior L, Waring P, Ahangari F, Lu SL, Chen P, Misko I, Paterson C, Kay G, Smorodinsky NI, Shiloh Y, Lavin MF. Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype. Cancer Research 2001, 61: 4561-8. PMID: 11389091.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisAtaxia TelangiectasiaAtaxia Telangiectasia Mutated ProteinsBase SequenceCell Cycle ProteinsCrosses, GeneticDNADNA-Binding ProteinsFemaleHumansLymphomaMaleMiceMice, Inbred C57BLMice, KnockoutMice, Mutant StrainsMutagenesis, Site-DirectedPhenotypeProtein Serine-Threonine KinasesSequence DeletionThymus NeoplasmsTumor Suppressor ProteinsUp-RegulationConceptsAtaxia telangiectasiaFrame deletionDisorder ataxia-telangiectasiaProtein kinase activityCell cycle checkpointsAmino acid residuesSelectable marker cassetteDetectable ATM proteinMutant proteinsATM proteinCycle checkpointsHomologous recombinationKinase activityAcid residuesMarker cassetteCommon deletion mutationsDeletion mutationsDeletion resultsCre-loxPATM geneThymic lymphomasExtensive apoptosisVariant phenotypesDifferent phenotypesFas ligand