Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
VIB Center for Inflammation Research, 9000 Ghent, Belgium.
Int J Mol Sci. 2024 Oct 15;25(20):11079. doi: 10.3390/ijms252011079.
Sepsis remains a huge unmet medical need for which no approved drugs, besides antibiotics, are on the market. Despite the clinical impact of sepsis, its molecular mechanism remains inadequately understood. Recent insights have shown that profound hepatic transcriptional reprogramming, leading to fatal metabolic abnormalities, might open a new avenue to treat sepsis. Translation of experimental results from rodents to larger animal models of higher relevance for human physiology, such as pigs, is critical and needs exploration. We performed a comparative analysis of the transcriptome profiles in murine and porcine livers using the following sepsis models: cecal ligation and puncture (CLP) in mice and fecal instillation (FI) in pigs, both of which induce polymicrobial septic peritonitis, and lipopolysaccharide (LPS)-induced endotoxemia in pigs, inducing sterile inflammation. Using bulk RNA sequencing, Metascape pathway analysis, and HOMER transcription factor motif analysis, we were able to identify key genes and pathways affected in septic livers. Conserved upregulated pathways in murine CLP and porcine LPS and FI generally comprise typical inflammatory pathways, except for ER stress, which was only found in the murine CLP model. Conserved pathways downregulated in sepsis comprise almost exclusively metabolic pathways such as monocarboxylic acid, steroid, biological oxidation, and small-molecule catabolism. Even though the upregulated inflammatory pathways were equally induced in the two porcine models, the porcine FI model more closely resembles the metabolic dysfunction observed in the CLP liver compared to the porcine LPS model. This comprehensive comparison focusing on the hepatic responses in mouse CLP versus LPS or FI in pigs shows that the two porcine sepsis models generally resemble quite well the mouse CLP model, with a typical inflammatory signature amongst the upregulated genes and metabolic dysfunction amongst the downregulated genes. The hepatic ER stress observed in the murine model could not be replicated in the porcine models. When studying metabolic dysfunction in the liver upon sepsis, the porcine FI model more closely resembles the mouse CLP model compared to the porcine LPS model.
脓毒症仍然是一个巨大的未满足的医学需求，除了抗生素之外，市场上没有批准的药物。尽管脓毒症具有临床影响，但它的分子机制仍未得到充分理解。最近的研究表明，深刻的肝脏转录重编程导致致命的代谢异常，可能为治疗脓毒症开辟新途径。将实验结果从啮齿动物转化为与人类生理学更相关的更大动物模型，如猪，是至关重要的，需要探索。我们使用以下脓毒症模型对鼠和猪肝脏的转录组谱进行了比较分析：小鼠的盲肠结扎和穿刺（CLP）和猪的粪便灌输（FI），两者均诱导多微生物性脓毒症腹膜炎，以及猪的脂多糖（LPS）诱导的内毒素血症，诱导无菌性炎症。使用批量 RNA 测序、Metascape 途径分析和 HOMER 转录因子基序分析，我们能够确定受脓毒症肝脏影响的关键基因和途径。在鼠 CLP 和猪 LPS 和 FI 中上调的保守途径通常包括典型的炎症途径，除了内质网应激，这仅在鼠 CLP 模型中发现。下调的保守途径几乎完全包括代谢途径，如单羧酸、类固醇、生物氧化和小分子分解代谢。尽管在两种猪模型中同样诱导了上调的炎症途径，但与猪 LPS 模型相比，猪 FI 模型更能模拟 CLP 肝脏中观察到的代谢功能障碍。这种全面比较聚焦于鼠 CLP 与 LPS 或 FI 对猪肝脏的反应表明，两种猪脓毒症模型通常与鼠 CLP 模型非常相似，上调基因中有典型的炎症特征，下调基因中有代谢功能障碍。在猪模型中不能复制在鼠模型中观察到的肝脏内质网应激。在研究脓毒症时肝脏的代谢功能障碍，与猪 LPS 模型相比，猪 FI 模型更能模拟鼠 CLP 模型。
