Department of Neuroscience, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ, USA.
Mayo Clinic Graduate School of Biomedical Sciences, Scottsdale, AZ, USA.
J Neuroinflammation. 2024 Jan 4;21(1):9. doi: 10.1186/s12974-023-03002-6.
Sepsis is a life-threatening state that arises due to a hyperactive inflammatory response stimulated by infection and rarely other insults (e.g., non-infections tissue injury). Although changes in several proinflammatory cytokines and signals are documented in humans and small animal models, far less is known about responses within affected tissues of large animal models. We sought to understand the changes that occur during the initial stages of inflammation by administering intravenous lipopolysaccharide (LPS) to Yorkshire pigs and assessing transcriptomic alterations in the brain, kidney, and whole blood. Robust transcriptional alterations were found in the brain, with upregulated responses enriched in inflammatory pathways and downregulated responses enriched in tight junction and blood vessel functions. Comparison of the inflammatory response in the pig brain to a similar mouse model demonstrated some overlapping changes but also numerous differences, including oppositely dysregulated genes between species. Substantial changes also occurred in the kidneys following LPS with several enriched upregulated pathways (cytokines, lipids, unfolded protein response, etc.) and downregulated gene sets (tube morphogenesis, glomerulus development, GTPase signal transduction, etc.). We also found significant dysregulation of genes in whole blood that fell into several gene ontology categories (cytokines, cell cycle, neutrophil degranulation, etc.). We observed a strong correlation between the brain and kidney responses, with significantly shared upregulated pathways (cytokine signaling, cell death, VEGFA pathways) and downregulated pathways (vasculature and RAC1 GTPases). In summary, we have identified a core set of shared genes and pathways in a pig model of systemic inflammation.
败血症是一种危及生命的状态，由于感染和很少其他刺激（例如，非感染性组织损伤）引起的过度活跃的炎症反应而产生。尽管在人类和小动物模型中已经记录了几种促炎细胞因子和信号的变化，但对于大型动物模型中受影响组织内的反应知之甚少。我们试图通过向约克夏猪静脉内给予脂多糖（LPS）来了解炎症初始阶段发生的变化，并评估大脑、肾脏和全血中的转录组变化。在大脑中发现了强大的转录变化，上调的反应富集在炎症途径中，而下调的反应富集在紧密连接和血管功能中。猪大脑炎症反应与类似的小鼠模型的比较表明存在一些重叠的变化，但也存在许多差异，包括物种之间的基因表达失调相反。在 LPS 作用下，肾脏也发生了大量变化，其中包括几个上调的途径（细胞因子、脂质、未折叠蛋白反应等）和下调的基因集（管状形态发生、肾小球发育、GTPase 信号转导等）。我们还发现全血中存在大量基因失调，这些失调基因分为几个基因本体类别（细胞因子、细胞周期、中性粒细胞脱粒等）。我们观察到大脑和肾脏反应之间存在很强的相关性，具有显著共享的上调途径（细胞因子信号、细胞死亡、VEGFA 途径）和下调途径（血管系统和 RAC1 GTPases）。总之，我们在系统性炎症的猪模型中确定了一组核心的共享基因和途径。
