2020
IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression
Stein S, Henze L, Poch T, Carambia A, Krech T, Preti M, Schuran FA, Reich M, Keitel V, Fiorotto R, Strazzabosco M, Fischer L, Li J, Müller LM, Wagner J, Gagliani N, Herkel J, Schwinge D, Schramm C. IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression. Journal Of Hepatology 2020, 74: 919-930. PMID: 33197512, PMCID: PMC8778963, DOI: 10.1016/j.jhep.2020.10.035.Peer-Reviewed Original ResearchConceptsIL-17A/FIL-17PD-L1T cellsOT-1Mouse modelAutoimmune cholestatic liver diseaseCell death ligand 1Cholangiocyte organoidsMajor histocompatibility complex IBile duct inflammationAntigen-specific CD8Bile duct injuryPD-L1 expressionDeath ligand 1Driver of inflammationTreatment of cholangitisCholestatic liver diseaseResponse of miceImportant protective effectDuct inflammationExperimental cholangitisDuct injuryAdoptive transferCytotoxic CD8
2018
Animal models of cholestasis: An update on inflammatory cholangiopathies
Mariotti V, Cadamuro M, Spirli C, Fiorotto R, Strazzabosco M, Fabris L. Animal models of cholestasis: An update on inflammatory cholangiopathies. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2018, 1865: 954-964. PMID: 30398152, DOI: 10.1016/j.bbadis.2018.07.025.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAnimal modelsPro-fibrotic signalsChronic liver diseasePrimary biliary cholangitisBile duct ligationFrequent clinical conditionBiliary injuryBiliary cholangitisBiliary obstructionLiver diseaseBiliary epitheliumDuct ligationInflammatory cholangiopathyAdaptive immunityClinical conditionsControversial diseasePathogenetic sequenceCholangiopathyCholestasisExperimental modelCholangitisDiseasePrimary targetChemical inductionCell elements
2017
The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma
Cadamuro M, Stecca T, Brivio S, Mariotti V, Fiorotto R, Spirli C, Strazzabosco M, Fabris L. The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1435-1443. PMID: 28757170, PMCID: PMC6386155, DOI: 10.1016/j.bbadis.2017.07.028.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsTumor reactive stromaReactive stromaMain cellular componentsDeleterious interplayCyto/chemokinesCellular componentsParacrine signalsPrognosis of cholangiocarcinomaTumor epithelial cellsCell interactionsEarly invasivenessJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenDifferent cell elementsEpithelial cellsEpithelial malignanciesTumor behaviorTumor epitheliumGrowth factorNeoplastic cellsTumor progressionCentral roleStromal componentsPathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium
Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E, Scirpo R, Fabris L. Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1374-1379. PMID: 28754453, PMCID: PMC5785585, DOI: 10.1016/j.bbadis.2017.07.023.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsToll-like receptorsLiver damageCystic fibrosis-related liver diseaseInnate immunityDamage-associated molecular patternsEpithelial innate immunityPro-inflammatory behaviorBiliary epithelial cellsNumber of receptorsJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenLiver injuryLiver diseaseBile flowInflammatory processBiliary epitheliumInflammatory responsePathophysiologic implicationsReparative processesNumber of evidencesFirst defense lineCholangiocytesMolecular patterns
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
2015
Ezrin finds its groove in cholangiocytes
Fouassier L, Fiorotto R. Ezrin finds its groove in cholangiocytes. Hepatology 2015, 61: 1467-1470. PMID: 25545157, PMCID: PMC4406785, DOI: 10.1002/hep.27675.Commentaries, Editorials and Letters
2013
Protein kinase a‐dependent pSer675‐β‐catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis
Spirli C, Locatelli L, Morell CM, Fiorotto R, Morton SD, Cadamuro M, Fabris L, Strazzabosco M. Protein kinase a‐dependent pSer675‐β‐catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology 2013, 58: 1713-1723. PMID: 23744610, PMCID: PMC3800498, DOI: 10.1002/hep.26554.Peer-Reviewed Original ResearchConceptsAutosomal recessive polycystic kidney diseaseCongenital hepatic fibrosisCaroli's diseaseΒ-cateninHepatic fibrosisRac-1 inhibitionIntrahepatic bile ductsRecessive polycystic kidney diseasePotential therapeutic targetPolycystic kidney diseaseStimulation of cAMPRac-1 activityE-cadherin expressionBile ductKidney diseaseLiver pathologyCystic dysplasiaMouse modelTherapeutic targetTranscriptional activityNuclear translocationDiseasePKA blockerCholangiocytesFibrosis
2012
Cyclic AMP/PKA‐dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin‐2 defective mice treated with sorafenib
Spirli C, Morell CM, Locatelli L, Okolicsanyi S, Ferrero C, Kim AK, Fabris L, Fiorotto R, Strazzabosco M. Cyclic AMP/PKA‐dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin‐2 defective mice treated with sorafenib. Hepatology 2012, 56: 2363-2374. PMID: 22653837, PMCID: PMC3460040, DOI: 10.1002/hep.25872.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, HormonalBenzenesulfonatesBile DuctsCaspase 3Cell ProliferationCells, CulturedCyclic AMP-Dependent Protein KinasesCystsDrug Therapy, CombinationEpithelial CellsKi-67 AntigenLiver DiseasesMAP Kinase Signaling SystemMiceMice, KnockoutNiacinamideOctreotidePhenylurea CompoundsPhosphorylationProtein Kinase InhibitorsProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-rafPyridinesSorafenibTRPP Cation ChannelsConceptsRaf-1Cell proliferationB-RafPhosphorylated ERKRaf kinase activitySignal-regulated kinase 1/2 pathwayRAF inhibitorsCyclic adenosine monophosphateRaf/MEK/ERKCyst growthDefective miceKinase 1/2 pathwayParadoxical activationCAMP/PKAMEK/ERKPolycystin-2Kinase AKinase activityWT cellsDependent activationERK1/2 phosphorylationInhibitor 14Epithelial cellsAdenosine monophosphateERKAltered store operated calcium entry increases cyclic 3′,5′‐adenosine monophosphate production and extracellular signal‐regulated kinases 1 and 2 phosphorylation in polycystin‐2‐defective cholangiocytes
Spirli C, Locatelli L, Fiorotto R, Morell CM, Fabris L, Pozzan T, Strazzabosco M. Altered store operated calcium entry increases cyclic 3′,5′‐adenosine monophosphate production and extracellular signal‐regulated kinases 1 and 2 phosphorylation in polycystin‐2‐defective cholangiocytes. Hepatology 2012, 55: 856-868. PMID: 21987453, PMCID: PMC3272110, DOI: 10.1002/hep.24723.Peer-Reviewed Original ResearchMeSH KeywordsAdenylyl CyclasesAnimalsBile DuctsCalciumCalcium ChannelsCalcium SignalingCells, CulturedCyclic AMPCyclic AMP-Dependent Protein KinasesHomeostasisMembrane GlycoproteinsMiceMice, KnockoutMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Models, AnimalPhosphorylationSignal TransductionStromal Interaction Molecule 1TRPP Cation ChannelsVascular Endothelial Growth Factor AConceptsSensor stromal interaction molecule 1Adenylyl cyclase type 6Extracellular signal-regulated kinases 1Signal-regulated kinases 1Overproduction of cAMPStromal interaction molecule 1Orai channelsWild-type miceSOCE activationCAMP productionRapamycin (mTOR) signalingKinase 1ERK pathwayERK1/2 activationHuman diseasesWT cellsMammalian targetDependent activationSTIM-1CAMP/Inappropriate activationCyst growthCystic cholangiocytesPolycystic liver diseaseActivation
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
2009
Diferentially expressed adenylyl cyclase isoforms mediate secretory functions in cholangiocyte subpopulation
Strazzabosco M, Fiorotto R, Melero S, Glaser S, Francis H, Spirli C, Alpini G. Diferentially expressed adenylyl cyclase isoforms mediate secretory functions in cholangiocyte subpopulation. Hepatology 2009, 50: 244-252. PMID: 19444869, PMCID: PMC2738985, DOI: 10.1002/hep.22926.Peer-Reviewed Original ResearchConceptsSoluble adenylyl cyclaseAdenylyl cyclasesGene expressionAC isoformsCyclic adenosine monophosphateAC gene expressionDifferent tissue specificitiesGroup of enzymesAdenylyl cyclase isoformsTissue specificityCholangiocyte secretionCyclase isoformsIsoformsSAC inhibitorIsohydric changesAdenylyl cyclaseIsoform expressionSACS geneReal-time polymerase chain reactionGenesAdenosine monophosphateAC8ExpressionCAMP levelsCAMP production
2007
Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development
Fabris L, Cadamuro M, Libbrecht L, Raynaud P, Spirlì C, Fiorotto R, Okolicsanyi L, Lemaigre F, Strazzabosco M, Roskams T. Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology 2007, 47: 719-728. PMID: 18157837, DOI: 10.1002/hep.22015.Peer-Reviewed Original ResearchConceptsVascular endothelial growth factorHepatic arteryAngiogenic growth factorsBile ductAngiopoietin-1Tie-2Growth factorAngiopoietin-2VEGFR-1Endothelial cellsMural cellsCognate receptorsIntrahepatic bile ductsClose anatomical relationshipFetal human liverDifferent gestational agesEndothelial growth factorDifferent maturational stagesGestational ageHuman liver developmentImmunohistochemical expressionDuctal plateEpithelial expressionPortal vasculatureArtery
2006
Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases
Fabris L, Cadamuro M, Fiorotto R, Roskams T, Spirlì C, Melero S, Sonzogni A, Joplin RE, Okolicsanyi L, Strazzabosco M. Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases. Hepatology 2006, 43: 1001-1012. PMID: 16628643, DOI: 10.1002/hep.21143.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseVascular endothelial growth factorPolycystic liver diseaseAng-1Liver diseaseDuctal platePortal vasculatureAng-2 gene expressionTie-2Expression of VEGFEmbryonic ductal plateDuctal plate cellsEffects of VEGFDominant polycystic kidney diseaseLiver cyst growthEndothelial growth factorAutocrine proliferative effectsPolycystic kidney diseaseLiver involvementADPKD mouse modelBiliary cystsCaroli's diseaseKidney diseaseADPKD patientsAng-2
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