title: Inhibition of Prolyl Hydroxylase Attenuates Fas Ligand-Induced Apoptosis and Lung Injury in Mice.
abstract: 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.
authors: 1 Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
authors: Yusuke
authors: Y
authors: Nagamine
authors: 1 Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
authors: Kentaro
authors: 0000-0002-1194-8636
authors: K
authors: Tojo
authors: 2 Department of Diagnostic Pathology, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan; and.
authors: Takuya
authors: T
authors: Yazawa
authors: 1 Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
authors: Shunsuke
authors: S
authors: Takaki
authors: 3 Operation Department, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan.
authors: Yasuko
authors: Y
authors: Baba
authors: 1 Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
authors: Takahisa
authors: T
authors: Goto
authors: 1 Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
authors: Kiyoyasu
authors: K
authors: Kurahashi
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D053222:Fas Ligand Protein / Q000494:pharmacology*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000600:Amino Acids, Dicarboxylic; C505534:Fadd protein, mouse; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; D053148:Caspase 3; C040947:oxalylglycine
keywords: Fas; acute respiratory distress syndrome; apoptosis; hypoxia-inducible factor; prolyl hydroxylase