Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure
Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure
复制标题
DOI：
10.1152/ajpregu.00432.2003
复制
发表时间：
2004-03-01
影响因子：
2.8
通讯作者：
Singer, M
中科院分区：
文献类型：
--
作者：
Brealey, D;Karyampudi, S;Singer, M
尽管脓毒症是危重症患者死亡和发病的主要原因，但导致多器官功能障碍的确切机制仍不清楚。在脓毒症患者和动物中发现的氧利用受损表明一氧化氮介导的线粒体呼吸链抑制作用。我们最近报道了脓毒性休克患者的骨骼肌线粒体功能障碍、临床严重程度和不良预后之间的关系。因此，我们利用雄性Wistar大鼠建立了一种长期的、液体复苏的粪便性腹膜炎模型，该模型密切复制了人类的生理、生化和组织学发现，死亡率为40%。与人类一样，器官功能障碍的严重程度和最终的不良预后与一氧化氮过量产生和日益加重的线粒体功能障碍（复合物I抑制和ATP耗竭）有关。这在重要器官（肝脏）和非重要器官（骨骼肌）中均可见到。同样，缺乏细胞死亡的组织学证据，这表明细胞功能可能适应性程序性关闭。因此，这项研究支持严重脓毒症诱导的多器官功能障碍具有生物能量病因学这一假设。尽管实验室模型存在公认的局限性，但我们发现这种长期模型与人类疾病特征之间存在明显的相似之处，这将有助于未来的转化研究。
Although sepsis is the major cause of mortality and morbidity in the critically ill, precise mechanism(s) causing multiorgan dysfunction remain unclear. Findings of impaired oxygen utilization in septic patients and animals implicate nitric oxide-mediated inhibition of the mitochondrial respiratory chain. We recently reported a relationship between skeletal muscle mitochondrial dysfunction, clinical severity, and poor outcome in patients with septic shock. We thus developed a long-term, fluid-resuscitated, fecal peritonitis model utilizing male Wistar rats that closely replicates human physiological, biochemical, and histological findings with a 40% mortality. As with humans, the severity of organ dysfunction and eventual poor outcome were associated with nitric oxide overproduction and increasing mitochondrial dysfunction (complex I inhibition and ATP depletion). This was seen in both vital (liver) and nonvital (skeletal muscle) organs. Likewise, histological evidence of cell death was lacking, suggesting the possibility of an adaptive programmed shutdown of cellular function. This study thus supports the hypothesis that multiorgan dysfunction induced by severe sepsis has a bioenergetic etiology. Despite the well-recognized limitations of laboratory models, we found clear parallels between this long-term model and human disease characteristics that will facilitate future translational research.