RNA-seq analysis of LPS-induced transcriptional changes and its possible implications for the adrenal gland dysregulation during sepsis
RNA-seq analysis of LPS-induced transcriptional changes and its possible implications for the adrenal gland dysregulation during sepsis
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DOI：
10.1016/j.jsbmb.2019.04.009
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发表时间：
2019-07-01
影响因子：
4.1
通讯作者：
Kanczkowski, Waldemar
中科院分区：
文献类型：
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作者：
Chen, Lan-Sun;Singh, Sumeet Pal;Kanczkowski, Waldemar
肾上腺应激反应的激活对于脓毒症的生存至关重要。实验和临床证据表明，由于脓毒症，肾上腺经常发生功能和结构损伤，其机制在很大程度上仍不清楚。在本研究中，我们使用RNA测序（RNA-Seq）技术来分析由细菌LPS阐明的肾上腺转录组的变化。我们的目的是发现以前没有报道的在脓毒症背景下参与肾上腺失调的基因的特别改变。我们的研究结果表明，与盐水注射的动物相比，全身给予LPS显著改变了8458个基因的表达。随后对这些基因签名的质量和功能分析显示，LPS诱导的高度同源的转录反应总共上调4312个基因和下调4146个基因。此外，功能注释分析和基因富集集分析（GSEA）清楚地表明，肾上腺对LPS的反应涉及与炎症反应相关的多个途径的改变，沿着先前未探索的缺氧途径的激活。此外，LPS强烈下调参与肾上腺稳态，发育和再生的基因。这些改变随后在临床相关的盲肠结扎穿孔（CLP）诱导的脓毒症模型中得到验证。总的来说，我们的研究表明，RNA-seq是一种非常有用的方法，可用于寻找脓毒症期间可能涉及肾上腺失调的新的未探索途径。
Activation of the adrenal gland stress response is of utmost importance to survive sepsis. Experimental and clinical evidence exists demonstrating that adrenal gland often develops functional and structural damage due to sepsis with mechanisms remaining largely unknown. In the present study, we have used RNA Sequencing (RNA-Seq) technology to analyze changes in adrenal transcriptome elucidated by bacterial LPS. We aimed to find particularly alterations in genes that were previously not reported to be involved in the adrenal gland dysregulation in contexts of sepsis. Our results demonstrate that systemic administration of LPS significantly altered expression of 8458 genes as compared to saline injected animals. The subsequent quality and functional analysis of these gene signatures revealed that LPS-induced highly homogenous transcriptional response in total upregulating 4312 and downregulating 4146 genes. Furthermore, functional annotation analysis together with gene enrichment set analysis (GSEA) clearly demonstrated that adrenal response to LPS involved alterations in multiple pathways related to the inflammatory response along with previously unexplored activation of the hypoxia pathway. In addition, LPS strongly downregulated genes involved in the adrenal homeostasis, development, and regeneration. Those alterations were subsequently verified in clinically relevant cecal ligation and puncture (CLP)-induced sepsis model. Collectively, our study demonstrates that RNA-seq is a very useful method that can be applied to search for new unexplored pathways potentially involved in adrenal gland dysregulation during sepsis.