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      Gene Expression Profiling Identifies Cell Proliferation and Inflammation as the Predominant Pathways Regulated by Aryl Hydrocarbon Receptor in Primary Human Fetal Lung Cells Exposed to Hyperoxia

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          Exposure to hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. We observed that aryl hydrocarbon receptor (AhR) signaling protects newborn mice and primary fetal human pulmonary microvascular endothelial cells (HPMECs) against hyperoxic injury. Additionally, a recent genome-wide transcriptome study in a newborn mouse model of BPD identified AhR as a key regulator of hyperoxia-induced gene dysregulation. Whether the AhR similarly deregulates genes in HPMEC is unknown. Therefore, the objective of this study was to characterize transcriptome level gene expression profile in AhR-sufficient and -deficient HPMEC exposed to normoxic and hyperoxic conditions. Global gene expression profiling was performed using Illumina microarray platform and selected genes were validated by real-time RT-PCR. AhR gene expression and hyperoxia independently affected the expression of 540 and 593 genes, respectively. Two-way ANOVA further identified 85 genes that were affected by an interaction between AhR expression and exposure to hyperoxia. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology, and Reactome pathway analysis identified cell proliferation, immune function, cytokine signaling, and organ development as the major pathways affected in AhR-deficient cells. The biological processes that were significantly enriched by hyperoxia included metabolic process, stress response, signal transduction, cell cycle, and immune regulation. Cell cycle was the predominant pathway affected by the combined effect of AhR knockdown and hyperoxia. Functional analysis of cell cycle showed that AhR-deficient cells had decreased proliferation compared with AhR-sufficient cells. These findings suggest that AhR modulates hyperoxic lung injury by regulating the genes that are necessary for cell proliferation and inflammation.

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          Author and article information

          Toxicol Sci
          Toxicol. Sci
          Toxicological Sciences
          Oxford University Press
          July 2016
          21 April 2016
          : 152
          : 1
          : 155-168
          *Department of Pediatrics, Section of Neonatal-Perinatal Medicine;
          Department of Molecular and Cell Biology
          Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
          Author notes
          1To whom correspondence should be addressed at Division of Neonatal-Perinatal Medicine, Texas Children’s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, Texas 77030. Fax: 832-825-3204. E-mail: shivanna@ 123456bcm.edu .
          PMC4922543 PMC4922543 4922543 kfw071
          © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
          Page count
          Pages: 14
          Aryl Hydrocarbon Receptor-Mediated Inflammation and Cell Proliferation in Lung Cells Exposed to High Oxygen


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