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基因表达谱分析确定细胞增殖和炎症是暴露于高氧环境的原代人胎儿肺细胞中芳烃受体调控的主要途径。

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.

作者信息

Shivanna Binoy, Maity Suman, Zhang Shaojie, Patel Ananddeep, Jiang Weiwu, Wang Lihua, Welty Stephen E, Belmont John, Coarfa Cristian, Moorthy Bhagavatula

机构信息

*Department of Pediatrics, Section of Neonatal-Perinatal Medicine; *Department of Pediatrics, Section of Neonatal-Perinatal Medicine;

Department of Molecular and Cell Biology.

出版信息

Toxicol Sci. 2016 Jul;152(1):155-68. doi: 10.1093/toxsci/kfw071. Epub 2016 Apr 21.

Abstract

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.

摘要

暴露于高氧环境会促使早产儿发生支气管肺发育不良(BPD)。我们观察到芳烃受体(AhR)信号通路可保护新生小鼠和原代人胎儿肺微血管内皮细胞(HPMECs)免受高氧损伤。此外,最近在BPD新生小鼠模型中进行的全基因组转录组研究将AhR确定为高氧诱导基因失调的关键调节因子。AhR是否同样会使HPMEC中的基因失调尚不清楚。因此,本研究的目的是表征在常氧和高氧条件下AhR充足和缺乏的HPMEC中转录组水平的基因表达谱。使用Illumina微阵列平台进行全基因组基因表达谱分析,并通过实时RT-PCR验证所选基因。AhR基因表达和高氧分别独立影响540个和593个基因的表达。双向方差分析进一步确定了85个受AhR表达与高氧暴露之间相互作用影响的基因。京都基因与基因组百科全书(KEGG)、基因本体论和Reactome通路分析确定细胞增殖、免疫功能、细胞因子信号传导和器官发育是AhR缺陷细胞中受影响的主要通路。高氧显著富集的生物学过程包括代谢过程、应激反应、信号转导、细胞周期和免疫调节。细胞周期是受AhR敲低和高氧联合作用影响的主要通路。细胞周期的功能分析表明,与AhR充足的细胞相比,AhR缺陷的细胞增殖减少。这些发现表明,AhR通过调节细胞增殖和炎症所需的基因来调节高氧性肺损伤。

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