Mattick John Sa, Yang Qian, Orman Mehmet A, Ierapetritou Marianthi G, Berthiaume Francois, Gale Stephen C, Androulakis Ioannis P
Chemical and Biochemical Engineering Department, Rutgers, the State University of New Jersey Piscataway, NJ, 08854, USA.
Int J Burns Trauma. 2013;3(1):55-65. Epub 2013 Jan 24.
Previously, we have shown that systemic insults in single injury models produced immunosuppressive effects in burn, and a strong acute phase response in sepsis through hepatic gene expression. In order to investigate the implications of these effects on a combined injury, a double hit model was explored to mimic the progression of clinical burn-sepsis. Rodents were subjected to a 20% total body surface area (TSA) full-thickness burn injury, and 48 hours later underwent cecal ligation and puncture (CLP) to induce sepsis. Pathways related to innate immune signaling through cytokines and NF-KB were co regulated with xenobiotic metabolism genes and acute phase protein genes, and that these genes were suppressed early, and then activated. Furthermore, we were able to identify that, in addition to amino acid metabolism, pyruvate metabolism, fatty acid metabolism and NRF-2 mediated oxidative stress genes were down regulated over the time course. Overall, these observed trends within the double hit burn-sepsis model represent unique immune and metabolic pathways and dynamics not found in either injury, including an early suppression followed by overreaction of pro inflammatory mediators, and an increase in amino acid metabolism at the expense of central carbon pathways.
此前，我们已经表明，在单一损伤模型中，全身性损伤在烧伤中产生免疫抑制作用，并通过肝脏基因表达在脓毒症中引发强烈的急性期反应。为了研究这些效应在复合损伤中的意义，我们探索了一种双打击模型来模拟临床烧伤脓毒症的进展。对啮齿动物进行20%体表面积（TSA）的全层烧伤，48小时后进行盲肠结扎和穿刺（CLP）以诱导脓毒症。通过细胞因子和NF-κB的先天性免疫信号传导相关途径与外源性代谢基因和急性期蛋白基因共同调节，并且这些基因早期被抑制，然后被激活。此外，我们能够确定，除了氨基酸代谢外，丙酮酸代谢、脂肪酸代谢和NRF-2介导的氧化应激基因在整个时间过程中均被下调。总体而言，在双打击烧伤脓毒症模型中观察到的这些趋势代表了在单一损伤中未发现的独特免疫和代谢途径及动态变化，包括促炎介质的早期抑制随后过度反应，以及以中枢碳途径为代价的氨基酸代谢增加。
