Role of increased sphingomyelinase activity in apoptosis and organ failure of patients with severe sepsis
Role of increased sphingomyelinase activity in apoptosis and organ failure of patients with severe sepsis
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DOI：
10.1096/fj.04-2842fje
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发表时间：
2005-07-01
期刊：
影响因子：
4.8
通讯作者：
Deigner, HP
中科院分区：
文献类型：
--
作者：
Claus, RA;Bunck, AC;Deigner, HP
许多研究支持这样的观点，即鞘磷脂酶的激活和随后的生物活性脂质介质神经酰胺的浓度增加在炎症刺激的协调和炎症期间诱导细胞凋亡中是至关重要的。在此，我们发现，与对照组相比，严重脓毒症患者表现出增强的鞘氨醇分解活性[ 262 pmol/（ml × h）vs. 123.6 pmol/（ml × h），P < 0.005]。在临床过程中，疾病的严重程度和致死性结局进一步增加。此外，我们表明，氧化应激可能部分占通过翻译后修饰的酶的活性增加。在小鼠内毒素休克模型中，给予低分子量抑制剂减少了酶活性的升高，提高了存活率。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，即激活的血浆异构体的鞘磷脂酶可能发挥关键作用的发展，细胞凋亡和器官衰竭的脓毒症。应进一步探索抑制分泌型鞘磷脂酶亚型作为解决败血症复杂难题的潜在靶点。
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.