Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA.
Department of Biostatistics, College of Medicine, University of Florida, Gainesville, FL, USA.
FASEB J. 2021 Feb;35(2):e21156. doi: 10.1096/fj.202002150R. Epub 2020 Nov 2.
Historically, murine models of inflammation in biomedical research have been shown to minimally correlate with genomic expression patterns from blood leukocytes in humans. In 2019, our laboratory reported an improved surgical sepsis model of cecal ligation and puncture (CLP) that provides additional daily chronic stress (DCS), as well as adhering to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. This model phenotypically recapitulates the persistent inflammation, immunosuppression, and catabolism syndrome observed in adult human surgical sepsis survivors. Whether these phenotypic similarities between septic humans and mice are replicated at the circulating blood leukocyte transcriptome has not been demonstrated. Our analysis, in contrast with previous findings, demonstrated that genome-wide expression in our new murine model more closely approximated human surgical sepsis patients, particularly in the more chronic phases of sepsis. Importantly, our new model of murine surgical sepsis with chronic stress did not reflect well gene expression patterns from humans with community-acquired sepsis. Our work indicates that improved preclinical murine sepsis modeling can better replicate both the phenotypic and transcriptomic responses to surgical sepsis, but cannot be extrapolated to other sepsis etiologies. Importantly, these improved models can be a useful adjunct to human-focused and artificial intelligence-based forms of research in order to improve septic patients' morbidity and mortality.
从历史上看，生物医学研究中的炎症小鼠模型与人类血液白细胞的基因组表达模式相关性极小。2019 年，我们实验室报告了一种改进的盲肠结扎穿刺（CLP）手术脓毒症模型，该模型提供了额外的日常慢性应激（DCS），并符合临床前脓毒症研究的最低质量阈值（MQTiPSS）指南。该模型在表型上再现了成人手术脓毒症幸存者中观察到的持续炎症、免疫抑制和分解代谢综合征。在循环血液白细胞转录组中是否复制了脓毒症患者和小鼠之间的这些表型相似性尚未得到证明。与之前的发现相反，我们的分析表明，我们新的小鼠模型中的全基因组表达更接近人类手术脓毒症患者，特别是在脓毒症的更慢性阶段。重要的是，我们新的慢性应激小鼠手术脓毒症模型不能很好地反映社区获得性脓毒症患者的基因表达模式。我们的工作表明，改进的临床前小鼠脓毒症模型可以更好地复制手术脓毒症的表型和转录组反应，但不能外推到其他脓毒症病因。重要的是，这些改进的模型可以作为以人类为中心和基于人工智能的研究的有用辅助手段，以提高脓毒症患者的发病率和死亡率。
