Badawi Sally, Paccalet Alexandre, Harhous Zeina, Pillot Bruno, Augeul Lionel, Van Coppenolle Fabien, Lachuer Joel, Kurdi Mazen, Crola Da Silva Claire, Ovize Michel, Bidaux Gabriel
INSERM 1060, INRA 1397, INSA Lyon, CarMeN Laboratory, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
IHU OPeRa, Groupement Hospitalier EST, Bron, France.
Front Physiol. 2019 Oct 31;10:1370. doi: 10.3389/fphys.2019.01370. eCollection 2019.
Ischemic heart diseases are a major cause of death worldwide. Different animal models, including cardiac surgery, have been developed over time. Unfortunately, the surgery models have been reported to trigger an important inflammatory response that might be an effect modifier, where involved molecular processes have not been fully elucidated yet.
We sought to perform a thorough characterization of the sham effect in the myocardium and identify the interfering inflammatory reaction in order to avoid misinterpretation of the data via systems biology approaches.
We combined a comprehensive analytical pipeline of mRNAseq dataset and systems biology analysis to characterize the acute phase response of mouse myocardium at 0 min, 45 min, and 24 h after surgery to better characterize the molecular processes inadvertently induced in sham animals. Our analysis showed that the surgical intervention induced 1209 differentially expressed transcripts (DETs). The clustering of positively co-regulated transcript modules at 45 min fingerprinted the activation of signalization pathways, while positively co-regulated genes at 24 h identified the recruitment of neutrophils and the differentiation of macrophages. In addition, we combined the prediction of transcription factors (TF) regulating DETs with protein-protein interaction networks built from these TFs to predict the molecular network which have induced the DETs. By mean of this retro-analysis of processes upstream gene transcription, we revealed a major role of the Il-6 pathway and further confirmed a significant increase in circulating IL-6 at 45 min after surgery.
This study suggests that a strong induction of the IL-6 axis occurs in sham animals over the first 24 h and leads to the induction of inflammation and tissues' homeostasis processes.
缺血性心脏病是全球主要的死亡原因。随着时间的推移，已经开发出了不同的动物模型，包括心脏手术模型。不幸的是，据报道手术模型会引发重要的炎症反应，这可能是一个效应修饰因素，其中涉及的分子过程尚未完全阐明。
我们试图对心肌中的假手术效应进行全面表征，并识别干扰性炎症反应，以避免通过系统生物学方法对数据产生误解。
我们结合了mRNAseq数据集的综合分析流程和系统生物学分析，以表征小鼠心肌在手术后0分钟、45分钟和24小时的急性期反应，从而更好地表征假手术动物中意外诱导的分子过程。我们的分析表明，手术干预诱导了1209个差异表达转录本（DETs）。45分钟时正向共调节转录本模块的聚类描绘了信号通路的激活，而24小时时正向共调节基因则识别出中性粒细胞的募集和巨噬细胞的分化。此外，我们将调节DETs的转录因子（TF）预测与由这些TF构建的蛋白质-蛋白质相互作用网络相结合，以预测诱导DETs的分子网络。通过对基因转录上游过程的这种逆向分析，我们揭示了Il-6通路的主要作用，并进一步证实了手术后45分钟循环IL-6显著增加。
本研究表明，在假手术动物中，IL-6轴在最初24小时内被强烈诱导，并导致炎症和组织稳态过程的诱导。
