Landscape of transcription and long non-coding RNAs reveals new insights into the inflammatory and fibrotic response following ventilator-induced lung injury.
Landscape of transcription and long non-coding RNAs reveals new insights into the inflammatory and fibrotic response following ventilator-induced lung injury.
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转录和长非编码RNA的景观揭示了呼吸机引起的肺损伤后炎症和纤维化反应的新见解
DOI：
10.1186/s12931-018-0822-z
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发表时间：
2018-06-22
影响因子：
5.8
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Wang L;Zhang N;Zhang Y;Xia J;Zhan Q;Wang C
机械通气可引起呼吸机诱导的肺损伤（VILI）和肺纤维化;然而，其潜在机制仍不完全清楚。RNA测序是在全基因组范围内检测至关重要的蛋白质编码转录本和长链非编码RNA（lncRNA）的有力手段，这可能有助于缩小这一知识差距。将90只C57 BL/6小鼠进行高潮气量通气或假手术，然后将通气的小鼠随机分配到0、1、3、5、7、14、21或28天的恢复期。测定肺组织病理学、湿干重比、羟脯氨酸浓度和转化生长因子β 1（TGF-β1）水平，以评价炎症和纤维化的进展。为了比较假手术肺以及通气后0天和7天的肺，使用RNA测序来阐明炎症和纤维化中涉及的表达模式、生物学过程和功能途径。明确的纤维化反应在通气后第7天最明显。假手术组和VILI组之间的成对比较显示，共有1297个差异表达的转录本（DET）。基因本体论分析确定刺激反应和免疫反应分别是参与炎症和纤维化的最重要因素。京都基因百科全书和基因组分析显示，雷帕霉素（mTOR），Janus激酶信号转导和转录激活因子的机制靶点，（JAK/STAT）和环磷酸腺苷（cAMP）信号转导与早期炎症有关;而TGF-β，缺氧诱导因子-1（HIF-1），Toll样受体（TLR），活化B细胞κ轻链增强子（NF-κB）信号通路参与了纤维化的发生。此外，在细胞和生物调节过程中鉴定并富集了332个DE lncRNA。这些lncRNA可能通过无翅/整合酶-1（Wnt）、HIF-1和TLR等信号通路调节纤维化。这是第一个转录组研究，以揭示所有的转录表达模式和关键途径参与VILI纤维化过程的基础上早期炎症状态，并显示重要的DE lncRNA调节炎症和纤维化。总之，本研究的结果为VILI和随后的纤维化的潜在分子机制提供了新的视角。本文的在线版本（10.1186/s12931-018-0822-z）包含补充材料，可供授权用户使用。
Mechanical ventilation can cause ventilator-induced lung injury (VILI) and lung fibrosis; however, the underlying mechanisms are still not fully understood. RNA sequencing is a powerful means for detecting vitally important protein-coding transcripts and long non-coding RNAs (lncRNAs) on a genome-wide scale, which may be helpful for reducing this knowledge gap. Ninety C57BL/6 mice were subjected to either high tidal volume ventilation or sham operation, and then mice with ventilation were randomly allocated to periods of recovery for 0, 1, 3, 5, 7, 14, 21, or 28 days. Lung histopathology, wet-to-dry weight ratio, hydroxyproline concentration, and transforming growth factor beta 1 (TGF-β1) levels were determined to evaluate the progression of inflammation and fibrosis. To compare sham-operated lungs, and 0- and 7-day post-ventilated lungs, RNA sequencing was used to elucidate the expression patterns, biological processes, and functional pathways involved in inflammation and fibrosis. A well-defined fibrotic response was most pronounced on day 7 post-ventilation. Pairwise comparisons among the sham and VILI groups showed a total of 1297 differentially expressed transcripts (DETs). Gene Ontology analysis determined that the stimulus response and immune response were the most important factors involved in inflammation and fibrosis, respectively. Kyoto Encyclopedia of Genes and Genomes analysis revealed that mechanistic target of rapamycin (mTOR), Janus kinase-signal transducer and activator of transcription (JAK/STAT), and cyclic adenosine monophosphate (cAMP) signaling were implicated in early inflammation; whereas TGF-β, hypoxia inducible factor-1 (HIF-1), Toll-like receptor (TLR), and kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways were significantly involved in subsequent fibrosis. Additionally, 332 DE lncRNAs were identified and enriched in the processes of cellular and biological regulation. These lncRNAs may potentially regulate fibrosis through signaling pathways such as wingless/integrase-1 (Wnt), HIF-1, and TLR. This is the first transcriptome study to reveal all of the transcript expression patterns and critical pathways involved in the VILI fibrotic process based on the early inflammatory state, and to show the important DE lncRNAs regulated in inflammation and fibrosis. Together, the results of this study provide novel perspectives into the potential molecular mechanisms underlying VILI and subsequent fibrosis. The online version of this article (10.1186/s12931-018-0822-z) contains supplementary material, which is available to authorized users.
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WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
2.5
作者：
Chen, Chin-Ming;Cheng, Kuo-Chen;Zhang, Haibo
通讯作者：
Zhang, Haibo
影响因子：
14.9
作者：
Kanehisa M;Araki M;Goto S;Hattori M;Hirakawa M;Itoh M;Katayama T;Kawashima S;Okuda S;Tokimatsu T;Yamanishi Y
通讯作者：
Yamanishi Y
影响因子：
158.5
作者：
Amato, MBP;Barbas, CSV;Carvalho, CRR
通讯作者：
Carvalho, CRR
DOI：
10.1093/bioinformatics/btr209
发表时间：
2011-07-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Lin MF;Jungreis I;Kellis M
通讯作者：
Kellis M