2025
Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis
Sakuma I, Gaspar R, Nasiri A, Dufour S, Kahn M, Zheng J, LaMoia T, Guerra M, Taki Y, Kawashima Y, Yimlamai D, Perelis M, Vatner D, Petersen K, Huttasch M, Knebel B, Kahl S, Roden M, Samuel V, Tanaka T, Shulman G. Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2502978122. PMID: 40310463, PMCID: PMC12067271, DOI: 10.1073/pnas.2502978122.Peer-Reviewed Original ResearchConceptsCholine-deficient l-amino acid-defined high-fat dietBempedoic acidLiver fibrosisLiver diseaseL-amino acid-defined high-fat dietAdvanced liver diseaseCholesterol contentHSD17B13 variantsHigh-fat dietTotal liver cholesterol contentTreated miceActivate signaling pathwaysVariant rs738409Liver cholesterol contentLiver lipidsFibrotic responsePromote inflammationTherapeutic approachesSteatotic liver diseaseDietary cholesterol supplementationFibrosisHuman liver samplesI148MAntisense oligonucleotidesProgressive form
2019
SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis
Tang H, Mao J, Ye X, Zhang F, Kerr W, Zheng T, Zhu Z. SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis. The FASEB Journal 2019, 34: 2011-2023. PMID: 31907997, PMCID: PMC7449602, DOI: 10.1096/fj.201902063r.Peer-Reviewed Original ResearchConceptsMouse lung endothelial cellsLung fibrosisFibrotic responseHuman umbilical vein endothelial cellsMiR-155Endothelial cellsKnockout miceMiR-155 knockout micePrimary mouse lung endothelial cellsMiR-155KO miceSHIP-1Spontaneous lung inflammationPro-inflammatory factorsLung fibrosis modelEndothelial-mesenchymal transitionLung endothelial cellsUmbilical vein endothelial cellsPI3K/AktTGF-β1 stimulationJAK/STAT3Lung inflammationVein endothelial cellsInositol phosphatase-1BLM challengeFibrosis modelSH2 domain-containing Phosphatase-(SHP)-2 blunts fibrotic responses through regulation of fibroblast mitochondrial metabolism and autophagy
Tzouvelekis A, Yu G, Ahangari F, Bennett A, Karampitsakos T, Bouros D, Bouros E, Kaminski N. SH2 domain-containing Phosphatase-(SHP)-2 blunts fibrotic responses through regulation of fibroblast mitochondrial metabolism and autophagy. 2019, pa583. DOI: 10.1183/13993003.congress-2019.pa583.Peer-Reviewed Original ResearchChitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3
Lee CM, He CH, Park JW, Lee JH, Kamle S, Ma B, Akosman B, Cotez R, Chen E, Zhou Y, Herzog EL, Ryu C, Peng X, Rosas IO, Poli S, Bostwick CF, Choi AM, Elias JA, Lee CG. Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3. Life Science Alliance 2019, 2: e201900350. PMID: 31085559, PMCID: PMC6516052, DOI: 10.26508/lsa.201900350.Peer-Reviewed Original ResearchMeSH KeywordsFibroblastsForkhead Box Protein O3Gene Expression RegulationGenes, ReporterHexosaminidasesHumansImmunohistochemistryIntracellular Signaling Peptides and ProteinsPromoter Regions, GeneticPulmonary FibrosisRNA, Small InterferingSignal TransductionSmad7 ProteinTransforming Growth Factor betaConceptsTGF-β1 signalingPulmonary fibrosisTGF-β1 inductionTGF-β1Idiopathic pulmonary fibrosisInterstitial lung diseaseTGF-β1/TGF-β receptorLung diseaseEffector responsesFibrotic responseTissue fibrosisFibrosisCritical mediatorCritical roleBox O3Protein 1DiseaseSmad7Tissue responseFOXO3TGFBRAP1Chitinase 1InductionPathway
2018
Impact of Cigarette Smoke Exposure on the Lung Fibroblastic Response after Influenza Pneumonia
Lee SW, Sharma L, Kang YA, Kim SH, Chandrasekharan S, Losier A, Brady V, Bermejo S, Andrews N, Yoon CM, Liu W, Lee JY, Kang MJ, Dela Cruz CS. Impact of Cigarette Smoke Exposure on the Lung Fibroblastic Response after Influenza Pneumonia. American Journal Of Respiratory Cell And Molecular Biology 2018, 59: 770-781. PMID: 30110182, PMCID: PMC6293077, DOI: 10.1165/rcmb.2018-0004oc.Peer-Reviewed Original ResearchConceptsCigarette smoke exposureLungs of miceInfluenza infectionInfluenza virusBAL fluidSmoke exposureGrowth factor-β1 levelsAir-exposed lungsInfluenza-infected miceSignificant lung injuryFibroblastic responseLung-derived fibroblastsProtein-positive cellsGrowth factor-β1Influenza pneumoniaDifferent time pointsLung injurySmoking groupSignificant morbidityCS exposureMurine modelFibrotic responseΒ1 levelsFactor-β1Weight recoveryThe Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis
Desai O, Winkler J, Minasyan M, Herzog EL. The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis. Frontiers In Medicine 2018, 5: 43. PMID: 29616220, PMCID: PMC5869935, DOI: 10.3389/fmed.2018.00043.BooksIdiopathic pulmonary fibrosisPulmonary fibrosisDanger-associated molecular patternsInnate immune populationsMolecular patternsMyeloid suppressor cellsInnate lymphoid cellsProfessional immune cellsT helper cellsAdaptive immune responsesRole of ImmuneAdaptive immune processesPathogen-associated molecular patternsImmunopathogenic mechanismsSuppressor cellsImmune activationInflammatory cellsImmune populationsImmune cellsDisease outcomeImmune responseFibrotic responsePotential therapyLymphoid cellsHuman studies
2015
IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells
Brodeur TY, Robidoux TE, Weinstein JS, Craft J, Swain SL, Marshak-Rothstein A. IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells. The Journal Of Immunology 2015, 195: 5251-5260. PMID: 26519529, PMCID: PMC4655158, DOI: 10.4049/jimmunol.1500777.Peer-Reviewed Original ResearchAntifibrotic Therapies in the Liver
Mehal W, Schuppan D. Antifibrotic Therapies in the Liver. Seminars In Liver Disease 2015, 35: 184-198. PMID: 25974903, PMCID: PMC5743222, DOI: 10.1055/s-0035-1550055.Peer-Reviewed Original ResearchConceptsAntifibrotic therapyIdeal patient populationRegression of fibrosisBest noninvasive methodFibrolytic propertiesDose titrationClinical outcomesFibrosis regressionPulmonary fibrosisPatient populationCombination therapyLiver fibrosisIndividualized therapyEncouraging dataFibrotic responseTherapeutic targetDrug AdministrationFibrosisTherapyNoninvasive methodInterindividual heterogeneityCell populationsAntifibroticsLiverFibrolysisThe Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor β Signaling
Wei J, Ghosh AK, Chu H, Fang F, Hinchcliff ME, Wang J, Marangoni RG, Varga J. The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor β Signaling. Arthritis & Rheumatology 2015, 67: 1323-1334. PMID: 25707573, PMCID: PMC4518870, DOI: 10.1002/art.39061.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCase-Control StudiesCells, CulturedDisease Models, AnimalEnzyme InhibitorsFibroblastsHumansMicep300-CBP Transcription FactorsPlatelet-Derived Growth FactorReal-Time Polymerase Chain ReactionResveratrolRNA, MessengerScleroderma, SystemicSignal TransductionSirtuin 1SkinSmad ProteinsStilbenesTransforming Growth Factor betaConceptsGenome-wide expression data setsTransforming Growth Factor β SignalingGrowth factor β signalingSSc skin biopsy samplesSirtuin 1Histone deacetylase sirtuin 1Tissue expressionExpression data setsPlatelet-derived growth factorTranscriptome dataDeacetylase sirtuin 1Epigenetic mechanismsAcetyltransferase p300Acetylation statusEnzyme sirtuin 1Persistent fibroblast activationEffect of SIRT1Β signalingMessenger RNA levelsMouse fibroblastsFibrotic responseLoss of SIRT1Activation of SIRT1Pharmacologic inhibitionExperimental fibrosis model
2014
Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors
Yuan A, Lee Y, Choi U, Moeckel G, Karihaloo A. Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors. American Journal Of Physiology. Renal Physiology 2014, 308: f459-f472. PMID: 25537742, PMCID: PMC4346747, DOI: 10.1152/ajprenal.00146.2014.Peer-Reviewed Original ResearchConceptsUnilateral ureteral obstructionCXCR4 expressionKidney fibrosisChemokine receptorsFibrotic responseSmooth muscle actin levelsG protein-coupled chemokine receptorsGrowth factorChronic kidney inflammationProgressive tissue injuryChronic kidney diseaseHigh CXCR4 expressionTGF-β1 levelsEffector cell typesProgression of fibrosisScarring/fibrosisFinal common pathwayPlatelet-derived growth factorRenal injuryKidney inflammationObstructed kidneysBone morphogenetic protein-7Renal fibrosisUreteral obstructionKidney diseaseFibronectinEDA Promotes Chronic Cutaneous Fibrosis Through Toll-Like Receptor Signaling
Bhattacharyya S, Tamaki Z, Wang W, Hinchcliff M, Hoover P, Getsios S, White ES, Varga J. FibronectinEDA Promotes Chronic Cutaneous Fibrosis Through Toll-Like Receptor Signaling. Science Translational Medicine 2014, 6: 232ra50. PMID: 24739758, PMCID: PMC4414050, DOI: 10.1126/scitranslmed.3008264.Peer-Reviewed Original ResearchConceptsToll-like receptor 4Endogenous TLR4 ligandsCutaneous fibrosisTLR4 ligandToll-like receptor signalingProgressive autoimmune diseaseLesional skin biopsiesFibronectin extra domain ATreatment of fibrosisTissue repair responseHallmark of sclerodermaPersistent fibroblast activationExtra domain ATLR4 blockadeAutoimmune diseasesChronic conditionsChronic fibrosisReceptor 4Skin biopsiesFibrotic responseOrganotypic skin equivalentsMultiple organsPotent stimulusSclerodermaFibroblast activation
2013
Gene expression profiles reveal molecular mechanisms involved in the progression and resolution of bleomycin-induced lung fibrosis
Cabrera S, Selman M, Lonzano-Bolaños A, Konishi K, Richards TJ, Kaminski N, Pardo A. Gene expression profiles reveal molecular mechanisms involved in the progression and resolution of bleomycin-induced lung fibrosis. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2013, 304: l593-l601. PMID: 23457188, PMCID: PMC4116413, DOI: 10.1152/ajplung.00320.2012.Peer-Reviewed Original ResearchConceptsLung fibrosisFibrotic responseResolution of bleomycinTranscriptional signatureGene expression profilesGene microarray analysisC57BL/6 miceProminent inflammationSingle doseExtracellular matrix-related genesInitial progressionControl animalsTIMP-1Normal architectureExpression profilesFibrosisMatrix metalloproteinasesHydroxyproline contentBleomycinMatrix-related genesSubsequent resolutionProgressionInflammationEqual volumeMicroarray analysis
2012
Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans
Yu G, Kovkarova-Naumovski E, Jara P, Parwani A, Kass D, Ruiz V, Lopez-Otín C, Rosas IO, Gibson KF, Cabrera S, Ramírez R, Yousem SA, Richards TJ, Chensny LJ, Selman M, Kaminski N, Pardo A. Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans. American Journal Of Respiratory And Critical Care Medicine 2012, 186: 752-762. PMID: 22859522, PMCID: PMC5450991, DOI: 10.1164/rccm.201202-0302oc.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBleomycinCells, CulturedCyclooxygenase 2Epithelial CellsGene Expression Regulation, EnzymologicHumansIdiopathic Pulmonary FibrosisLaser Capture MicrodissectionMatrix Metalloproteinases, SecretedMiceMice, KnockoutOligonucleotide Array Sequence AnalysisPulmonary AlveoliUp-RegulationConceptsIdiopathic pulmonary fibrosisHyperplastic epithelial cellsAlveolar epithelial cellsEpithelial cellsMMP-19IPF lungsWT miceLung fibrosisFibrotic responseHyperplastic alveolar epithelial cellsNovel mediatorLaser capture microscopeLung fibrotic responseDevelopment of fibrosisWild-type miceEpithelial phenotypic changesMatrix metalloproteinase-19Microarray analysisA549 epithelial cellsLung injuryBronchoalveolar lavagePulmonary fibrosisLung tissueSame lungFibrosisFibrosis in systemic sclerosis: common and unique pathobiology
Bhattacharyya S, Wei J, Tourtellotte WG, Hinchcliff M, Gottardi CG, Varga J. Fibrosis in systemic sclerosis: common and unique pathobiology. Fibrogenesis & Tissue Repair 2012, 5: s18. PMID: 23259815, PMCID: PMC3368774, DOI: 10.1186/1755-1536-5-s1-s18.Peer-Reviewed Original ResearchReactive oxygen speciesMesenchymal progenitor cell differentiationCellular differentiation programsProgenitor cell differentiationSystemic sclerosisTranscriptional activatorComplex polygenic diseaseDifferentiation programEpigenetic factorsFibroblast activationCell differentiationInnate immune receptorsImmune receptorsPolygenic diseaseBone marrow-derived fibrocytesUnique pathobiologyOxygen speciesGrowth factorOxidative stressSelective targetingDifferentiationObliterative vasculopathyPathobiologic featuresUncontrolled progressionFibrotic responseImatinib mesylate causes genome-wide transcriptional changes in systemic sclerosis fibroblasts in vitro.
Hinchcliff M, Huang CC, Ishida W, Fang F, Lee J, Jafari N, Wilkes M, Bhattacharyya S, Leof E, Varga J. Imatinib mesylate causes genome-wide transcriptional changes in systemic sclerosis fibroblasts in vitro. Clinical And Experimental Rheumatology 2012, 30: s86-96. PMID: 22691216, PMCID: PMC3860597.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzamidesBiopsyCase-Control StudiesCells, CulturedFibroblastsFibrosisGene Expression ProfilingGene Expression RegulationHumansImatinib MesylateMiceMice, KnockoutOligonucleotide Array Sequence AnalysisPhosphorylationPiperazinesProtein Kinase InhibitorsProto-Oncogene Proteins c-ablPyrimidinesScleroderma, SystemicSignal TransductionSkinTime FactorsTranscription, GeneticTransforming Growth Factor beta1ConceptsSystemic sclerosisSSc fibroblastsSkin biopsiesInternal organ fibrosisHeterogeneous multifactorial diseaseControl fibroblastsControl skin biopsiesFibrotic gene expressionSystemic sclerosis fibroblastsC-AblProgressive skinAntifibrotic effectsImatinib mesylateHealthy controlsCardiovascular diseaseGene expressionHealthy subjectsFibrotic responseCholesterol metabolismOrgan fibrosisC-Abl activationMultifactorial diseaseTreatment resultsTissue levelsFibrosis
2011
Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1
Schmitz JC, Protiva P, Gattu AK, Utsumi T, Iwakiri Y, Neto AG, Quinn M, Cornwell ML, Fitchev P, Lugea A, Crawford SE, Chung C. Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1. American Journal Of Pathology 2011, 179: 2990-2999. PMID: 21964188, PMCID: PMC3260804, DOI: 10.1016/j.ajpath.2011.08.009.Peer-Reviewed Original ResearchConceptsPigment epithelium-derived factorWild-type miceLoss of PEDFPEDF expressionQuantitative real-time PCRFibrotic responseNormal extracellular matrixWild-type animalsReal-time PCRSmooth muscle actin stainingExtracellular matrixIntragastric feeding modelMice fed ethanolPancreatitis responsesEarly fibrotic responseEpithelium-derived factorMuscle actin stainingSirius red stainingExpression levelsThrombospondin-1Actin stainingFibrogenic markersMore fibrosisPEDF overexpressionEthanol diet
2010
Recent advances in pulmonary fibrosis: implications for scleroderma
Homer RJ, Herzog EL. Recent advances in pulmonary fibrosis: implications for scleroderma. Current Opinion In Rheumatology 2010, 22: 683-689. PMID: 20693906, DOI: 10.1097/bor.0b013e32833ddcc9.BooksConceptsPulmonary fibrosisEpithelial cell injuryCell injuryIdiopathic pulmonary fibrosisRole of lymphocytesAlternative macrophage activationPathogenesis of sclerodermaTranslational human studiesEpithelial-mesenchymal transitionEndoplasmic reticulum stressMost patientsSystemic sclerosisLung fibrosisLymphocyte functionEffective therapyLeading causeLung parenchymaFibrotic responseHuman studiesMacrophage activationScar tissueFibrosisPossible associationAnimal modelingPatients
2009
Deletion of the Met receptor in the collecting duct decreases renal repair following ureteral obstruction
Ma H, Saenko M, Opuko A, Togawa A, Soda K, Marlier A, Moeckel GW, Cantley LG, Ishibe S. Deletion of the Met receptor in the collecting duct decreases renal repair following ureteral obstruction. Kidney International 2009, 76: 868-876. PMID: 19675527, DOI: 10.1038/ki.2009.304.Peer-Reviewed Original ResearchConceptsUreteral obstructionFibrotic responseKnockout miceMet receptorAcute tubular necrosisPlasminogen activator inhibitor-1Unilateral ureteral obstructionTubular cell proliferationActivator inhibitor-1Conditional knockout miceHepatocyte growth factorKidney injuryRenal injuryTubular necrosisFunctional recoveryInterstitial fibrosisCre miceRenal repairNephron injuryControl littermatesObstructionGrowth factorMiceInhibitor-1InjuryIncreased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury
Scotton CJ, Krupiczojc MA, Königshoff M, Mercer PF, Lee YC, Kaminski N, Morser J, Post JM, Maher TM, Nicholson AG, Moffatt JD, Laurent GJ, Derian CK, Eickelberg O, Chambers RC. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. Journal Of Clinical Investigation 2009, 119: 2550-2563. PMID: 19652365, PMCID: PMC2735922, DOI: 10.1172/jci33288.Peer-Reviewed Original ResearchMeSH KeywordsActinsAdultAgedAnimalsBase SequenceBleomycinCase-Control StudiesCell DifferentiationCells, CulturedFactor XaFactor Xa InhibitorsFemaleFibroblastsGene ExpressionHumansIdiopathic Pulmonary FibrosisLung InjuryMaleMiceMice, Inbred C57BLMiddle AgedModels, BiologicalPulmonary FibrosisReceptor, PAR-1Receptors, VitronectinRNA, MessengerTransforming Growth Factor betaUp-RegulationConceptsProteinase-activated receptor 1Lung injuryPulmonary fibrosisFibrotic responseCoagulation cascade contributesExcessive procoagulant activityChronic lung diseaseIdiopathic pulmonary fibrosisMurine lung injuryDirect FXa inhibitorsFibrotic lung tissueHuman adult lungFactor XTGF-beta activationNovel pathogenetic mechanismLung biopsyMicrovascular leakFibrotic fociLung diseaseFibrosis developmentLung tissuePathogenetic mechanismsAlpha-SMATissue injuryAlveolar epitheliumA non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate
Bhattacharyya S, Ishida W, Wu M, Wilkes M, Mori Y, Hinchcliff M, Leof E, Varga J. A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate. Oncogene 2009, 28: 1285-1297. PMID: 19151753, PMCID: PMC4006376, DOI: 10.1038/onc.2008.479.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzamidesBleomycinCells, CulturedCollagenEarly Growth Response Protein 1Extracellular Signal-Regulated MAP KinasesFibroblastsFibrosisHumansImatinib MesylateMiceMice, Inbred BALB CNIH 3T3 CellsPiperazinesProtein Kinase InhibitorsProto-Oncogene Proteins c-ablPyrimidinesSignal TransductionSmad2 ProteinSmad3 ProteinTransforming Growth Factor betaConceptsChronic myelogenous leukemiaFibrotic responseEgr-1Growth factorUpregulated tissue expressionFibrosis of skinNovel therapeutic approachesEarly growth response factor-1Kinase-deficient mutant formC-AblNormal fibroblastsTGF-β stimulationIntracellular signaling mechanismLesional skinStimulation of collagenImatinib mesylateMouse embryonic fibroblastsFibrotic processMyelogenous leukemiaTherapeutic approachesPharmacological targetingTarget of inhibitionTGF-β responseFibroblast activationC-Abl activation
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