Unknown,Transcriptomics,Genomics,Proteomics

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Anti-Inflammatory Effects of Budesonide in Human Fetal Lung

ABSTRACT: Rationale. Lung inflammation in premature infants contributes to development of bronchopulmonary dysplasia (BPD), a chronic lung disease with long-term sequelae. Pilot studies administering budesonide suspended in surfactant have found reduced BPD without apparent adverse effects as occur with systemic dexamethasone therapy. Objectives. To determine effects of budesonide on differential genes expression in human fetal lung Methods. We prepared RNA from 3 samples of human fetal lung at 23 weeks gestation before (preculture, PC) and after 4 days culture as explants with (Bud) or without (Way) budesonide (30 nM) and performed RNAseq on the 9 samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Philip Ballard

PROVIDER: E-GEOD-83888 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Antiinflammatory Effects of Budesonide in Human Fetal Lung.

Barrette Anne Marie AM Roberts Jessica K JK Chapin Cheryl C Egan Edmund A EA Segal Mark R MR Oses-Prieto Juan A JA Chand Shreya S Burlingame Alma L AL Ballard Philip L PL

American journal of respiratory cell and molecular biology 20161101 5

Lung inflammation in premature infants contributes to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease with long-term sequelae. Pilot studies administering budesonide suspended in surfactant have found reduced BPD without the apparent adverse effects that occur with systemic dexamethasone therapy. Our objective was to determine budesonide potency, stability, and antiinflammatory effects in human fetal lung. We cultured explants of second-trimester fetal lung with budes ...[more]

PMID: 27281349

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Project description: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 mice (cGrp78f/f) with lung epithelial cell-specific knockout (KO) of Grp78, a gene encoding the ER chaperone 78-kDa 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. cGrp78f/f pups died immediately after birth, likely due to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of pro-apoptotic transcription factor 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-Î² (TGF-Î²)/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress and TGF-Î²/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone taursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78f/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. Whole-genome expression profiling was performed using MouseRef-8 v2.0 Expression BeadChips (Illumina) on RNA isolated from lungs of four Grp78f/f and three cGrp78f/f mice at E18.

Dataset Information

Anti-Inflammatory Effects of Budesonide in Human Fetal Lung

Publications

Antiinflammatory Effects of Budesonide in Human Fetal Lung.

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