{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360004236537670656.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1165/rcmb.2015-0266oc"}},{"identifier":{"@type":"URI","@value":"https://academic.oup.com/ajrcmb/article-pdf/55/6/878/66823647/ajrcmb_55_6_878.pdf"}},{"identifier":{"@type":"PMID","@value":"27494234"}}],"resourceType":"学術雑誌論文(journal article)","dc:title":[{"@value":"Inhibition of Prolyl Hydroxylase Attenuates Fas Ligand–Induced Apoptosis and Lung Injury in Mice"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:title>Abstract</jats:title>\n                  <jats:p>Alveolar epithelial injury and increased alveolar permeability are hallmarks of acute respiratory distress syndrome. Apoptosis of lung epithelial cells via the Fas/Fas ligand (FasL) pathway plays a critical role in alveolar epithelial injury. Activation of hypoxia-inducible factor (HIF)-1 by inhibition of prolyl hydroxylase domain proteins (PHDs) is a possible therapeutic approach to attenuate apoptosis and organ injury. Here, we investigated whether treatment with dimethyloxalylglycine (DMOG), an inhibitor of PHDs, could attenuate Fas/FasL–dependent apoptosis in lung epithelial cells and lung injury. DMOG increased HIF-1α protein expression in vitro in MLE-12 cells, a murine alveolar epithelial cell line. Treatment of MLE-12 cells with DMOG significantly suppressed cell surface expression of Fas and attenuated FasL-induced caspase-3 activation and apoptotic cell death. Inhibition of the HIF-1 pathway by echinomycin or small interfering RNA transfection abolished these antiapoptotic effects of DMOG. Moreover, intraperitoneal injection of DMOG in mice increased HIF-1α expression and decreased Fas expression in lung tissues. DMOG treatment significantly attenuated caspase-3 activation, apoptotic cell death in lung tissue, and the increase in alveolar permeability in mice instilled intratracheally with FasL. In addition, inflammatory responses and histopathological changes were also significantly attenuated by DMOG treatment. In conclusion, inhibition of PHDs protects lung epithelial cells from Fas/FasL–dependent apoptosis through HIF-1 activation and attenuates lung injury in mice.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380004236537670785","@type":"Researcher","foaf:name":[{"@value":"Yusuke Nagamine"}],"jpcoar:affiliationName":[{"@value":"Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1420564276178790400","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"80737552"},{"@type":"NRID","@value":"1000080737552"},{"@type":"NRID","@value":"9000409875793"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/ktojo"}],"foaf:name":[{"@value":"Kentaro Tojo"}],"jpcoar:affiliationName":[{"@value":"Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236537670661","@type":"Researcher","foaf:name":[{"@value":"Takuya Yazawa"}],"jpcoar:affiliationName":[{"@value":"Department of Diagnostic Pathology, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan; and"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236537670658","@type":"Researcher","foaf:name":[{"@value":"Shunsuke Takaki"}],"jpcoar:affiliationName":[{"@value":"Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236537670790","@type":"Researcher","foaf:name":[{"@value":"Yasuko Baba"}],"jpcoar:affiliationName":[{"@value":"Operation Department, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236537670656","@type":"Researcher","foaf:name":[{"@value":"Takahisa Goto"}],"jpcoar:affiliationName":[{"@value":"Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236537670659","@type":"Researcher","foaf:name":[{"@value":"Kiyoyasu Kurahashi"}],"jpcoar:affiliationName":[{"@value":"Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"10441549"},{"@type":"EISSN","@value":"15354989"}],"prism:publicationName":[{"@value":"American Journal of Respiratory Cell and Molecular Biology"}],"dc:publisher":[{"@value":"Oxford University Press (OUP)"}],"prism:publicationDate":"2016-12-01","prism:volume":"55","prism:number":"6","prism:startingPage":"878","prism:endingPage":"888"},"reviewed":"false","dc:rights":["https://academic.oup.com/pages/standard-publication-reuse-rights"],"url":[{"@id":"https://academic.oup.com/ajrcmb/article-pdf/55/6/878/66823647/ajrcmb_55_6_878.pdf"}],"createdAt":"2016-08-05","modifiedAt":"2026-02-12","foaf:topic":[{"@id":"https://cir.nii.ac.jp/all?q=Male","dc:title":"Male"},{"@id":"https://cir.nii.ac.jp/all?q=Cell%20Membrane%20Permeability","dc:title":"Cell Membrane Permeability"},{"@id":"https://cir.nii.ac.jp/all?q=Fas%20Ligand%20Protein","dc:title":"Fas Ligand Protein"},{"@id":"https://cir.nii.ac.jp/all?q=Caspase%203","dc:title":"Caspase 3"},{"@id":"https://cir.nii.ac.jp/all?q=Protein%20Stability","dc:title":"Protein Stability"},{"@id":"https://cir.nii.ac.jp/all?q=Fas-Associated%20Death%20Domain%20Protein","dc:title":"Fas-Associated Death Domain Protein"},{"@id":"https://cir.nii.ac.jp/all?q=Procollagen-Proline%20Dioxygenase","dc:title":"Procollagen-Proline Dioxygenase"},{"@id":"https://cir.nii.ac.jp/all?q=Apoptosis","dc:title":"Apoptosis"},{"@id":"https://cir.nii.ac.jp/all?q=Lung%20Injury","dc:title":"Lung Injury"},{"@id":"https://cir.nii.ac.jp/all?q=Hypoxia-Inducible%20Factor%201,%20alpha%20Subunit","dc:title":"Hypoxia-Inducible Factor 1, alpha Subunit"},{"@id":"https://cir.nii.ac.jp/all?q=Amino%20Acids,%20Dicarboxylic","dc:title":"Amino Acids, Dicarboxylic"},{"@id":"https://cir.nii.ac.jp/all?q=Cell%20Line","dc:title":"Cell Line"},{"@id":"https://cir.nii.ac.jp/all?q=Mice,%20Inbred%20C57BL","dc:title":"Mice, Inbred C57BL"},{"@id":"https://cir.nii.ac.jp/all?q=Animals","dc:title":"Animals"},{"@id":"https://cir.nii.ac.jp/all?q=Humans","dc:title":"Humans"},{"@id":"https://cir.nii.ac.jp/all?q=Lung","dc:title":"Lung"},{"@id":"https://cir.nii.ac.jp/all?q=Signal%20Transduction","dc:title":"Signal Transduction"}],"project":[{"@id":"https://cir.nii.ac.jp/crid/1040282256841896832","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"15K20054"},{"@type":"JGN","@value":"JP15K20054"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15K20054/"}],"notation":[{"@language":"ja","@value":"肺胞上皮細胞における低酸素誘導性因子の機能解析と肺傷害治療開発に向けた基盤研究"},{"@language":"en","@value":"Hypoxia-Inducible Factor as a Therapeutic Target for Acute Respiratory Distress Syndrome"}]}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360004234785937536","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Enhancement of glycolysis by inhibition of oxygen‐sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury"}]},{"@id":"https://cir.nii.ac.jp/crid/1360011143614869888","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The Hydroxylase Inhibitor 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Gentamicin-Induced Acute Injury"}]},{"@id":"https://cir.nii.ac.jp/crid/1360848661256408960","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The Fas/FasL pathway impairs the alveolar fluid clearance in mouse lungs"}]},{"@id":"https://cir.nii.ac.jp/crid/1360855569605992448","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The acute respiratory distress syndrome"}]},{"@id":"https://cir.nii.ac.jp/crid/1360855569870026368","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Recombinant human Fas ligand induces alveolar epithelial cell apoptosis and lung injury in rabbits"}]},{"@id":"https://cir.nii.ac.jp/crid/1360855570515389952","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The biological activity of FasL in human and mouse lungs is determined by the structure of its stalk 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Sepsis"}]},{"@id":"https://cir.nii.ac.jp/crid/1361981470706348928","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Hydroxylase Inhibition Abrogates TNF-α–Induced Intestinal Epithelial Damage by Hypoxia-Inducible Factor-1–Dependent Repression of FADD"}]},{"@id":"https://cir.nii.ac.jp/crid/1362262943832814720","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity"}]},{"@id":"https://cir.nii.ac.jp/crid/1362262944103462272","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Apoptosis and Epithelial Injury in the Lungs"}]},{"@id":"https://cir.nii.ac.jp/crid/1362262944957171200","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Preconditional Activation of Hypoxia-Inducible Factors Ameliorates Ischemic Acute Renal Failure"}]},{"@id":"https://cir.nii.ac.jp/crid/1362262945171187328","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Fas/FasL-dependent Apoptosis of Alveolar Cells after Lipopolysaccharide-induced Lung Injury in Mice"}]},{"@id":"https://cir.nii.ac.jp/crid/1362262945907297408","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Mechanical ventilation-induced apoptosis in newborn rat lung is mediated via FasL/Fas pathway"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544418962937216","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Fas (CD95) Induces Alveolar Epithelial Cell Apoptosis in Vivo"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544419432005376","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Hypoxia: an alarm signal during intestinal inflammation"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544420252056960","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Hyperoxia-induced apoptosis and Fas/FasL expression in lung epithelial cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544421188024320","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"PHD Inhibition Mitigates and Protects Against Radiation-Induced Gastrointestinal Toxicity via HIF2"}]},{"@id":"https://cir.nii.ac.jp/crid/1362825893610063104","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388843781550720","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Inhibition of prolyl hydroxylases by dimethyloxaloylglycine after stroke reduces ischemic brain injury and requires hypoxia inducible factor-1α"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388843962823808","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388844008534272","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Preconditioned suppression of prolyl-hydroxylases attenuates renal injury but increases mortality in septic murine models"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388844485131776","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The Hydroxylase Inhibitor Dimethyloxallyl Glycine Attenuates Endotoxic Shock Via Alternative Activation of Macrophages and IL-10 Production by B1 Cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388845559748480","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice"}]},{"@id":"https://cir.nii.ac.jp/crid/1363670318352187520","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Production of immortalized distal respiratory epithelial cell lines from surfactant protein C/simian virus 40 large tumor antigen transgenic mice."}]},{"@id":"https://cir.nii.ac.jp/crid/1363670318526279296","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Depletion of PHD3 protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis"}]},{"@id":"https://cir.nii.ac.jp/crid/1363670318740115712","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Fas and Fas Ligand Are Up-Regulated in Pulmonary Edema Fluid and Lung Tissue of Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome"}]},{"@id":"https://cir.nii.ac.jp/crid/1363670319437124224","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"FADD: a regulator of life and death"}]},{"@id":"https://cir.nii.ac.jp/crid/1364233269709007744","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"HIF1A Reduces Acute Lung Injury by Optimizing Carbohydrate Metabolism in the Alveolar Epithelium"}]},{"@id":"https://cir.nii.ac.jp/crid/1364233270839031936","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Silencing of Fas, but Not Caspase-8, in Lung Epithelial Cells Ameliorates Pulmonary Apoptosis, Inflammation, and Neutrophil Influx after Hemorrhagic Shock and Sepsis"}]},{"@id":"https://cir.nii.ac.jp/crid/1370026061244269696","@type":"Product","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Dimethyloxalylglycine, a prolyl hydroxylase inhibitor, 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