title: The 78-kD Glucose-Regulated Protein Regulates Endoplasmic Reticulum Homeostasis and Distal Epithelial Cell Survival during Lung Development.
abstract: Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated conditional knockout (KO) mice (cGrp78(f/f)) with lung epithelial cell-specific KO of Grp78, a gene encoding the ER chaperone 78-kD glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis, and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78(f/f) pups died immediately after birth, likely owing to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of the proapoptotic transcription factor CCAAT/enhancer-binding proteins (C/EBP) homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-β/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress, and transforming growth factor-β/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone Tauroursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78(f/f) lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress, and suggest the UPR as a potential therapeutic target in BPD.
authors.affiliation: Departments of 1 Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine.
authors.forename: Per
authors.initials: P
authors.lastname: Flodby
authors.affiliation: 2 Pediatrics.
authors.forename: Changgong
authors.initials: C
authors.lastname: Li
authors.affiliation: Departments of 1 Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of 1 Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.affiliation: 3 Surgery, and.|4 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California.
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Marconett
authors.affiliation: 3 Surgery, and.|5 Biochemistry and Molecular Biology, and.|4 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California.
authors.forename: Ite A
authors.initials: IA
authors.lastname: Laird-Offringa
authors.affiliation: 2 Pediatrics.
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
authors.affiliation: 5 Biochemistry and Molecular Biology, and.|4 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Departments of 1 Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine.|4 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California.
authors.forename: Beiyun
authors.initials: B
authors.lastname: Zhou
mesh_terms: D056809:Alveolar Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D012333:RNA, Messenger; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine
keywords: 78-kD glucose-regulated protein knockout; alveolar epithelial cells; apoptosis; endoplasmic reticulum stress/unfolded protein response signaling
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