Contribution of gene expression to metabolic fluxes in hypermetabolic livers induced through burn injury and cecal ligation and puncture in rats
Contribution of gene expression to metabolic fluxes in hypermetabolic livers induced through burn injury and cecal ligation and puncture in rats
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DOI：
10.1002/bit.21200
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发表时间：
2007-05-01
影响因子：
3.8
通讯作者：
Yarmush, Martin L.
中科院分区：
文献类型：
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作者：
Banta, Scott;Vemula, Murali;Yarmush, Martin L.
严重损伤激活了许多应激相关和炎症途径，可导致全身性高代谢状态。之前使用灌注的高代谢大鼠肝脏的研究已经确定了内在代谢通量的变化，这些变化不依赖于持续存在的应激激素和底物负荷升高。我们研究了这样的变化可能是由于基因表达的持续改变的假设。通过应用中度烧伤，2天后通过盲肠结扎和穿刺（CLP）产生脓毒症，在大鼠中诱导全身高代谢反应。对照动物接受假烧伤后CLP，或假烧伤后假CLP。CLP后两天，或假烧伤后假CLP。CLP后两天，使用DNA微阵列分析肝脏的基因表达变化，并通过离体灌注结合代谢通量分析分析肝脏的代谢改变。烧伤前CLP增加通量，而基因表达水平下降。相反，CLP单独显着增加代谢基因的表达，但减少了许多相应的代谢通量。烧伤合并CLP导致最显著的变化，其中通量和基因表达的同时变化，而CLP治疗通过转录机制上调代谢机制。总的来说，这些数据表明，通过DNA微阵列分析在单个时间点测量的mRNA变化在灌注的肝脏中不可靠地改变代谢通量。
Severe injury activates many stress-related and inflammatory pathways that can lead to a systemic hypermetabolic state. Prior studies using perfused hypermeatbolic rat livers have identified intrinsic metabolic flux changes that were not dependent upon the continual presence of elevated stress hormones and substrate loads. We investigated the hypothesis that such changes may be due to persistent alterations in gene expression. A systemic hypermetabolic response was induced in rats by applying a moderate burn injury followed 2 days later by cenum ligation and puncture (CLP) to produce sepsis. Control animals recieved a sham- burn followed by CLP, or a sham-burn followed by a sham-CLP. Two days after CLP, or a sham-burn followed by sham-CLP. Two days after CLP, livers were analyzed for gene expression changes using DNA microarrays and for metaboloism alterations by ex vivo perfusion coupled with Metabolic Flux Analysis. Burn injury prior to CLP increased fluxes while decreases in gene expression levels were observed. Conversely, CLP alone significantly increased metabolic gene expression, but decreased many decreased many of the corresponding metabolic fluxes. Burn injury combined with CLP led to the most dramatic changes, where concurrent changes in fluxes and gene expression, while CLP treatment up-regulated the metabolic machinery by transcriptional mechanisms. Overall, these data show that mRNA changes measured at a single time point by DNA microarray analysis do not reliably metabolic flux changes in perfused livers.