Claus Ralf A, Bunck Alexander C, Bockmeyer Clemens L, Brunkhorst Frank M, Lösche Wolfgang, Kinscherf Ralf, Deigner Hans-Peter
Department of Anaesthesiology and Intensive Care Medicine, Friedrich Schiller University Jena, Jena, Germany.
FASEB J. 2005 Oct;19(12):1719-21. doi: 10.1096/fj.04-2842fje. Epub 2005 Jul 28.
Numerous studies support the notion that an activation of sphingomyelinases and a subsequent increase of the concentration of the bioactive lipid mediator ceramide are critical in the concert of inflammatory stimuli and to the induction of apoptosis during inflammation. Here we show that patients with severe sepsis exhibit an enhanced sphingolytic activity in comparison with controls [262 pmol/(mlxh) vs. 123.6 pmol/(mlxh), P<0.005]. During the clinical course, a further increase was paralleled by the severity of illness and by fatal outcome. Moreover, we show that oxidative stress may partially account for the increased activity through posttranslational modification of the enzyme. In a murine endotoxic shock model, administration of a low molecular weight inhibitor diminished the rise in enzymatic activity and improved the survival rate. In liver specimen, inhibition of activity correlated with a reduced rate of hepato-cellular apoptosis. Our data support the concept that activation of the plasmatic isoform of sphingomyelinase may play a critical role in the development of apoptosis and organ failure in sepsis. An inhibition of the secreted isoform of sphingomyelinase should be explored further as a potential target in the complicated puzzle of sepsis.
众多研究支持这样一种观点，即鞘磷脂酶的激活以及随后生物活性脂质介质神经酰胺浓度的增加，在炎症刺激协同作用以及炎症期间诱导细胞凋亡过程中至关重要。在此我们表明，与对照组相比，严重脓毒症患者表现出增强的鞘脂分解活性[262 pmol/(ml·h) 对 123.6 pmol/(ml·h)，P<0.005]。在临床病程中，活性进一步增加与疾病严重程度及致命结局平行。此外，我们表明氧化应激可能通过对该酶的翻译后修饰部分解释了活性增加的原因。在小鼠内毒素休克模型中，给予低分子量抑制剂可减少酶活性的升高并提高存活率。在肝脏标本中，活性抑制与肝细胞凋亡率降低相关。我们的数据支持这样的概念，即血浆型鞘磷脂酶的激活可能在脓毒症中细胞凋亡和器官衰竭的发展中起关键作用。作为脓毒症复杂难题中的一个潜在靶点，应进一步探索对分泌型鞘磷脂酶的抑制作用。
