2024
Prominent role of gut dysbiosis in the pathogenesis of cystic fibrosis-related liver disease in mice
Bertolini A, Nguyen M, Zehra S, Taleb S, Bauer-Pisani T, Palm N, Strazzabosco M, Fiorotto R. Prominent role of gut dysbiosis in the pathogenesis of cystic fibrosis-related liver disease in mice. Journal Of Hepatology 2024, 81: 429-440. PMID: 38554847, PMCID: PMC11347101, DOI: 10.1016/j.jhep.2024.03.041.Peer-Reviewed Original ResearchCystic fibrosis-related liver diseaseCystic fibrosis transmembrane conductance regulatorCFTR-KO miceDefective cystic fibrosis transmembrane conductance regulatorCFTR-KOIntestinal permeabilityLiver diseaseGut-liver axisGut dysbiosisIncreased morbidityMortality of CF patientsAssociated with increased intestinal permeabilityLiver pathologyDevelopment of cholangiopathyCftr-knockout miceTransmembrane conductance regulatorIncreased intestinal permeabilityTargeted therapeutic strategiesFecal microbiota transferAttenuates liver diseaseExcessive inflammatory responseFITC-dextran assayPresence of neutrophilsActivation of pro-inflammatoryCFTR-knockout
2019
Pathophysiology of Cystic Fibrosis Liver Disease: A Channelopathy Leading to Alterations in Innate Immunity and in Microbiota
Fiorotto R, Strazzabosco M. Pathophysiology of Cystic Fibrosis Liver Disease: A Channelopathy Leading to Alterations in Innate Immunity and in Microbiota. Cellular And Molecular Gastroenterology And Hepatology 2019, 8: 197-207. PMID: 31075352, PMCID: PMC6664222, DOI: 10.1016/j.jcmgh.2019.04.013.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsCF-associated liver diseaseLiver diseaseCystic fibrosisInnate immunityCystic fibrosis liver diseaseEpithelial innate immunityCystic fibrosis transmembrane conductance regulatorFibrosis transmembrane conductance regulatorNonpulmonary causesCF adultsTransmembrane conductance regulatorLiver complicationsMutations of CFTRPediatric populationAltered microbiotaIntestinal diseaseBile secretionCF mortalityDiseaseNew drugsConductance regulatorPotential targetLife expectancyBasic defectPathophysiology
2018
Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy
Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M. Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy. Hepatology 2018, 67: 972-988. PMID: 28836688, PMCID: PMC5783790, DOI: 10.1002/hep.29400.Peer-Reviewed Original ResearchMeSH KeywordsAminophenolsAminopyridinesAnimalsBenzodioxolesBiliary TractCell Culture TechniquesChloride Channel AgonistsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorCytokinesCytoskeletonEpithelial CellsFluorescent Antibody TechniqueHumansInduced Pluripotent Stem CellsInflammationMiceMicroscopy, ConfocalPyrimidinesQuinolonesSignal TransductionSrc-Family KinasesConceptsBiliary epitheliumCystic fibrosisToll-like receptor 4Cystic fibrosis transmembrane conductance regulatorFluid secretionActivated B cells (NF-κB) activationClinical liver diseaseStrong translational potentialCause of deathB cell activationSrc kinase inhibitionFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorInflammatory changesPharmacological therapyProinflammatory changesProinflammatory chemokinesInflammation contributesLiver diseaseHuman cholangiopathiesReceptor 4Healthy controlsLiver patientsCF patientsVX-770
2016
The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity
Fiorotto R, Villani A, Kourtidis A, Scirpo R, Amenduni M, Geibel PJ, Cadamuro M, Spirli C, Anastasiadis PZ, Strazzabosco M. The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity. Hepatology 2016, 64: 2118-2134. PMID: 27629435, PMCID: PMC5115965, DOI: 10.1002/hep.28817.Peer-Reviewed Original ResearchConceptsBiliary epithelial cellsLiver diseaseToll-like receptor 4 activityToll-like receptor 4 responsesCystic fibrosis transmembrane conductance regulatorToll-like receptor 4Nuclear factorEpithelial cellsProinflammatory cytokine productionNovel therapeutic targetEpithelial barrier functionActivated B cellsFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorCytokine productionEpithelial inflammationInflammatory cellsInflammatory processReceptor 4Biliary damageInflammatory responseInflammatory cholangiopathyProtective effectBile secretionImmune pathways
2011
Loss of CFTR Affects Biliary Epithelium Innate Immunity and Causes TLR4–NF-κB—Mediated Inflammatory Response in Mice
Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, Strazzabosco M. Loss of CFTR Affects Biliary Epithelium Innate Immunity and Causes TLR4–NF-κB—Mediated Inflammatory Response in Mice. Gastroenterology 2011, 141: 1498-1508.e5. PMID: 21712022, PMCID: PMC3186841, DOI: 10.1053/j.gastro.2011.06.052.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Bacterial AgentsBile DuctsCholagogues and CholereticsCholangitisColitisCytokinesDextran SulfateDisease Models, AnimalEpithelial CellsHEK293 CellsHumansImmunity, InnateInflammation MediatorsKeratin-19Leukocyte Common AntigensLipopolysaccharidesMiceMice, Inbred C57BLMice, Inbred CFTRMice, KnockoutNeomycinNF-kappa BPhosphorylationPolymyxin BSrc-Family KinasesTime FactorsToll-Like Receptor 4TransfectionUrsodeoxycholic AcidConceptsCFTR KO miceBiliary epitheliumCystic fibrosisPortal inflammationBiliary damageInflammatory responseInnate immunityGut-derived bacterial productsTLR4 inhibitor TAK-242Toll-like receptor 4Cystic fibrosis transmembrane conductance regulatorInhibitor TAK-242Wild-type littermatesActivation of NFNuclear factor κBOral neomycinTLR4-NFTAK-242Liver damagePathogenetic roleBile flowDuctular reactionReceptor 4Cytokine secretionUrsodeoxycholic acid
2005
Glibenclamide Stimulates Fluid Secretion in Rodent Cholangiocytes Through a Cystic Fibrosis Transmembrane Conductance Regulator-Independent Mechanism
Spirlì C, Fiorotto R, Song L, Santos-Sacchi J, Okolicsanyi L, Masier S, Rocchi L, Vairetti MP, de Bernard M, Melero S, Pozzan T, Strazzabosco M. Glibenclamide Stimulates Fluid Secretion in Rodent Cholangiocytes Through a Cystic Fibrosis Transmembrane Conductance Regulator-Independent Mechanism. Gastroenterology 2005, 129: 220-233. PMID: 16012949, DOI: 10.1053/j.gastro.2005.03.048.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsATP-Binding Cassette TransportersBile DuctsBody FluidsCalciumCell LineCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorElectric CapacitanceElectric ConductivityGlyburideHypoglycemic AgentsLiverMiceMice, Inbred CFTRPatch-Clamp TechniquesPotassium ChannelsPotassium Channels, Inwardly RectifyingRatsReceptors, DrugSulfonylurea ReceptorsConceptsCystic fibrosisBiliary ductsCholangiocyte secretionFluid secretionAbility of glibenclamideCystic fibrosis transmembrane conductance regulatorIntracellular Ca 2Liver impairmentSevere complicationsLiver diseaseCholestatic diseaseRodent cholangiocytesGlibenclamideInhibitors of exocytosisAbstractTextFibrosisSecretionSecretory mechanismDiseaseMiceCholangiocytesRat cholangiocytesCFTR inhibitor
2003
Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes
Spirlì C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T, Larusso NF, Sonzogni A, Okolicsanyi L, Strazzabosco M. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology 2003, 124: 737-753. PMID: 12612912, DOI: 10.1053/gast.2003.50100.Peer-Reviewed Original ResearchMeSH KeywordsAdenylyl Cyclase InhibitorsAdenylyl CyclasesAnimalsBile DuctsBile Ducts, IntrahepaticCell LineCyclic AMPDrug SynergismGene ExpressionHumansInterferon-gammaIntracellular FluidIon TransportLiver DiseasesNitratesNitric OxideNitric Oxide DonorsNitric Oxide SynthaseNitric Oxide Synthase Type IINitritesRatsTumor Necrosis Factor-alphaConceptsPrimary sclerosing cholangitisProinflammatory cytokinesBiliary epitheliumAdenylyl cyclaseHuman chronic liver diseaseInducible nitric oxide synthaseChronic liver diseaseSecretory mechanismInhibition of ACNitric oxide synthaseTumor necrosis factorDependent fluid secretionReactive nitrogen oxide speciesCAMP-dependent secretionNOS-2 inhibitorCystic fibrosis transmembrane conductance regulatorCAMP-dependent ClDuctular cholestasisProgressive cholestasisSclerosing cholangitisLiver diseaseCholestatic effectLiver damageBile productionNOS2 induction
2001
Proinflammatory Cytokines Inhibit Secretion in Rat Bile Duct Epithelium
Spirlı̀ C, Nathanson M, Fiorotto R, Duner E, Denson L, Sanz J, Di Virgilio F, Okolicsanyi L, Casagrande F, Strazzabosco M. Proinflammatory Cytokines Inhibit Secretion in Rat Bile Duct Epithelium. Gastroenterology 2001, 121: 156-169. PMID: 11438505, DOI: 10.1053/gast.2001.25516.Peer-Reviewed Original ResearchConceptsProinflammatory cytokinesFluorescein-labeled dextranIL-1Interferon gammaCAMP-dependent fluid secretionCystic fibrosis transmembrane conductance regulatorBile duct epitheliumRat bile duct epitheliaTumor necrosis factorCyclic adenosine monophosphate levelsSecretin receptorAdenosine monophosphate levelsBile duct unitsDuctular cholestasisPortal inflammationCholestatic disordersIL-6Inflammatory cytokinesTNF-alphaBiliary epitheliumNecrosis factorCellular cyclic adenosine monophosphate (cAMP) levelsDuct epitheliumPurinergic agonistsSR expression