Inhibition of Prolyl Hydroxylase Attenuates Fas Ligand–Induced Apoptosis and Lung Injury in Mice
Male
Cell Membrane Permeability
Fas Ligand Protein
Caspase 3
Protein Stability
Fas-Associated Death Domain Protein
Procollagen-Proline Dioxygenase
Apoptosis
Lung Injury
Hypoxia-Inducible Factor 1, alpha Subunit
Amino Acids, Dicarboxylic
Cell Line
3. Good health
Mice, Inbred C57BL
Animals
Humans
Lung
Signal Transduction
DOI:
10.1165/rcmb.2015-0266oc
Publication Date:
2016-08-05T19:30:59Z
AUTHORS (7)
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.
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