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
Stimulation of nuclear receptor peroxisome proliferator–activated receptor‐γ limits NF‐κB‐dependent inflammation in mouse cystic fibrosis biliary epithelium
Scirpo R, Fiorotto R, Villani A, Amenduni M, Spirli C, Strazzabosco M. Stimulation of nuclear receptor peroxisome proliferator–activated receptor‐γ limits NF‐κB‐dependent inflammation in mouse cystic fibrosis biliary epithelium. Hepatology 2015, 62: 1551-1562. PMID: 26199136, PMCID: PMC4618241, DOI: 10.1002/hep.28000.Peer-Reviewed Original ResearchConceptsCystic fibrosis-associated liver diseaseNF-κB-dependent inflammationCFTR knockout miceLiver diseaseToll-like receptor-4/nuclear factor kappaB-cells inhibitor alphaCystic fibrosis transmembrane conductance regulator knockout miceKappa light polypeptide gene enhancerPeroxisome proliferator-activated receptorStimulation of PPARDextran sodium sulfateAnti-inflammatory effectsChronic inflammatory stateLight polypeptide gene enhancerNuclear receptorsNuclear factor kappaProliferator-activated receptorDependent immune mechanismQuality of lifeActivated B cellsCystic fibrosis patientsChronic cholangiopathiesInflammatory stateProinflammatory cytokinesPortal endotoxemia
2013
Platelet‐derived growth factor‐D and Rho GTPases regulate recruitment of cancer‐associated fibroblasts in cholangiocarcinoma
Cadamuro M, Nardo G, Indraccolo S, Dall'Olmo L, Sambado L, Moserle L, Franceschet I, Colledan M, Massani M, Stecca T, Bassi N, Morton S, Spirli C, Fiorotto R, Fabris L, Strazzabosco M. Platelet‐derived growth factor‐D and Rho GTPases regulate recruitment of cancer‐associated fibroblasts in cholangiocarcinoma. Hepatology 2013, 58: 1042-1053. PMID: 23505219, PMCID: PMC3732815, DOI: 10.1002/hep.26384.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBenzamidesBile Duct NeoplasmsBile Ducts, IntrahepaticCell Line, TumorCell MovementCell ProliferationCells, CulturedCholangiocarcinomaEpithelial-Mesenchymal TransitionFibroblastsHeterograftsHumansImatinib MesylateIn Vitro TechniquesLymphokinesMaleMiceMice, SCIDPiperazinesPlatelet-Derived Growth FactorPyrimidinesRho GTP-Binding ProteinsSignal TransductionConceptsCancer-associated fibroblastsPlatelet-derived growth factorEpithelial-mesenchymal transitionCCA cellsSecretion of PDGFRole of PDGFGrowth factorAbundant stromal reactionAlpha-smooth muscle actinPDGF-D expressionNovel therapeutic approachesPotential therapeutic targetSmooth muscle actinCCA cell linesPDGF-D signalingFibroblast migrationC-Jun N-terminal kinaseEMT biomarkersImmunodeficient miceStromal reactionTherapeutic approachesStroma interactionsTherapeutic targetCholangiocarcinomaMesenchymal markers
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
2009
ERK1/2-Dependent Vascular Endothelial Growth Factor Signaling Sustains Cyst Growth in Polycystin-2 Defective Mice
Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, Tian X, Somlo S, Strazzabosco M. ERK1/2-Dependent Vascular Endothelial Growth Factor Signaling Sustains Cyst Growth in Polycystin-2 Defective Mice. Gastroenterology 2009, 138: 360-371.e7. PMID: 19766642, PMCID: PMC3000794, DOI: 10.1053/j.gastro.2009.09.005.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedCyclic AMP-Dependent Protein KinasesCystsHypoxia-Inducible Factor 1, alpha SubunitIndolesLiver DiseasesMAP Kinase Signaling SystemMiceMice, KnockoutMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3PhenotypePhosphorylationProliferating Cell Nuclear AntigenProtein Kinase InhibitorsPyrrolesRepressor ProteinsTRPP Cation ChannelsTumor Suppressor ProteinsVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2ConceptsVascular endothelial growth factorPolycystic liver diseaseVEGF secretionLiver cystsLiver diseaseVEGFR-2Cyst growthLiver/body weight ratioAdult dominant polycystic kidney diseaseParacrine vascular endothelial growth factorSecretion of VEGFHIF-1alphaBody weight ratioEffects of VEGFAutocrine vascular endothelial growth factorDominant polycystic kidney diseaseExpression of pERKVascular endothelial growth factor signalingPhosphorylated VEGFR-2Liver cyst growthEndothelial growth factorPolycystic kidney diseaseCyst epithelial cellsExtracellular signal-regulated kinase 1/2Hypoxia-inducible factor
2001
Ductular morphogenesis and functional polarization of normal human biliary epithelial cells in three-dimensional culture
Ishida Y, Smith S, Wallace L, Sadamoto T, Okamoto M, Auth M, Strazzabosco M, Fabris L, Medina J, Prieto J, Strain A, Neuberger J, Joplin R. Ductular morphogenesis and functional polarization of normal human biliary epithelial cells in three-dimensional culture. Journal Of Hepatology 2001, 35: 2-9. PMID: 11495037, DOI: 10.1016/s0168-8278(01)00078-2.Peer-Reviewed Original ResearchConceptsCollagen gel cultureHuman biliary epithelial cellsEpithelial cellsGel cultureGrowth factorHuman hepatocyte growth factorThree-dimensional cultureBiliary epithelial cellsThree-dimensional aggregatesNormal human biliary epithelial cellsFoetal bovine serumMorphogenesisCell typesAnion exchanger 2Hepatocyte growth factorFunctional polarizationFunctional differentiationFunctional markersExchanger 2Monolayer culture systemCentral lumenPhenotypic markersCollagen gelsNumber of aggregatesCulture system
1997
Na+‐dependent and ‐independent Cl−/HCO exchange mediate cellular HCO transport in cultured human intrahepatic bile duct cells
Strazzabosco M, Joplin R, Zsembery A, Wallace L, Spirli C, Fabris L, Granato A, Rossanese A, Poci C, Neuberger J, Okolicsanyi L, Crepaldi G. Na+‐dependent and ‐independent Cl−/HCO exchange mediate cellular HCO transport in cultured human intrahepatic bile duct cells. Hepatology 1997, 25: 976-985. PMID: 9096607, DOI: 10.1002/hep.510250431.Peer-Reviewed Original ResearchConceptsEpithelial membrane antigenIntracellular acid loadHuman cholangiocytesAcid loadIntrahepatic bile duct cellsFactor VIII-related antigenIntracellular cyclic adenosine monophosphate (cAMP) concentrationsBiliary HCO3- secretionPediatric liver transplantationAdministration of agentsCyclic adenosine monophosphate concentrationsHuman hepatocyte growth factorVIII-related antigenBile duct cellsNormal liver tissueBiliary epithelial cellsCl- channel inhibitorsHepatocyte growth factorAdenosine monophosphate concentrationsIntracellular cAMP concentrationLiver transplantationReduced graftAbsence of HCO3Biliary treeAcid loader
1991
Cl(-)-HCO3- exchanger in isolated rat hepatocytes: role in regulation of intracellular pH
Benedetti A, Strazzabosco M, Corasanti J, Haddad P, Graf J, Boyer J. Cl(-)-HCO3- exchanger in isolated rat hepatocytes: role in regulation of intracellular pH. American Journal Of Physiology 1991, 261: g512-g522. PMID: 1887897, DOI: 10.1152/ajpgi.1991.261.3.g512.Peer-Reviewed Original ResearchMeSH Keywords4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic AcidAmmoniaAnimalsBariumBicarbonatesCarrier ProteinsCells, CulturedChloride-Bicarbonate AntiportersChloridesHydrogen-Ion ConcentrationIntracellular FluidKineticsLiverMaleRatsRats, Inbred StrainsConceptsAlkaline loadPH-sensitive dye BCECFMM H2DIDSPHi recoveryRegulation of intracellularRat hepatocyte monolayersAcid extrudersMM DIDSRat hepatocytesElectrophysiological techniquesDye BCECFHCO3- exchangerIsolated rat hepatocytesConstant pHoIntracellularMembrane potentialHepatocyte monolayersHepatocytesAcid loadingEffect of UDCA on intracellular and biliary pH in isolated rat hepatocyte couplets and perfused livers
Strazzabosco M, Sakisaka S, Hayakawa T, Boyer J. Effect of UDCA on intracellular and biliary pH in isolated rat hepatocyte couplets and perfused livers. American Journal Of Physiology 1991, 260: g58-g69. PMID: 1987808, DOI: 10.1152/ajpgi.1991.260.1.g58.Peer-Reviewed Original ResearchConceptsBiliary HCO3- concentrationUrsodeoxycholic acidRat hepatocyte coupletsBiliary pHAcid loadEffect of UDCABile duct lumenHepatocyte coupletsIsolated rat hepatocyte coupletsBiliary epitheliumHCO3- concentrationDuct lumenRemoval of ClHCO3- exchangeRat liverLiverIPRLHepatocytesHypercholeresisPerfusateBileExcretionEpitheliumAmiloride