Nos3 protects against systemic inflammation and myocardial dysfunction in murine polymicrobial sepsis.
Nos3 protects against systemic inflammation and myocardial dysfunction in murine polymicrobial sepsis.
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DOI：
10.1097/shk.0b013e3181cdc327
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Ichinose F
中科院分区：
文献类型：
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作者：
Bougaki M;Searles RJ;Kida K;Yu J;Buys ES;Ichinose F
一氧化氮（NO）与感染性休克的发病机制有关。然而，NO 合酶 3 (NOS3) 在脓毒症期间的作用仍不完全清楚。在此，我们研究了 NOS3 缺乏对腹膜炎诱导的多种微生物败血症期间全身炎症和心肌功能障碍的影响。在野生型 (WT) 和 NOS3 缺陷型 (NOS3KO) 小鼠中，结肠升支架腹膜炎 (CASP) 诱发严重的多种微生物败血症。 CASP 后，NOS3KO 小鼠的存活时间比 WT 小鼠短。根据肺、肝和心脏中炎性细胞因子的表达评估，NOS3 缺乏会加剧全身炎症。 CASP 显着增加了 NOS3KO 小鼠肝脏和心脏浸润的白细胞数量，但在 WT 小鼠中则不然。 CASP后22小时，与WT小鼠相比，脓毒症NOS3KO小鼠中过度的全身炎症与更明显的心肌功能障碍相关。 CASP 后 NOS3 缺乏对心肌功能的不利影响似乎是由心肌细胞的 Ca2+ 处理受损引起的。从接受 CASP 的 NOS3KO 小鼠中分离出的心肌细胞的 Ca2+ 处理受损与线粒体 ATP 生成减少有关，线粒体 ATP 生成是肌浆网 (SR) Ca2+-ATP 酶 Ca2+ 循环能力的决定因素。 CASP 后 NOS3 缺陷引起的线粒体产生 ATP 能力的损害至少部分归因于线粒体呼吸链复合物 I 活性的降低。这些观察结果表明，NOS3 可以防止小鼠腹膜炎诱导的多种微生物败血症后的全身炎症和心肌功能障碍。
Nitric oxide (NO) has been implicated in the pathogenesis of septic shock. However, the role of NO synthase 3 (NOS3) during sepsis remains incompletely understood. Here, we examined impact of NOS3 deficiency on systemic inflammation and myocardial dysfunction during peritonitis-induced polymicrobial sepsis. Severe polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type (WT) and NOS3-deficient (NOS3KO) mice. NOS3KO mice exhibited shorter survival time than did WT mice after CASP. NOS3 deficiency worsened systemic inflammation assessed by the expression of inflammatory cytokines in the lung, liver, and heart. CASP markedly increased the number of leukocyte infiltrating the liver and heart in NOS3KO but not in WT mice. The exaggerated systemic inflammation in septic NOS3KO mice was associated with more marked myocardial dysfunction than in WT mice 22h after CASP. The detrimental effects of NOS3-deficiency on myocardial function after CASP appear to be caused by impaired Ca2+ handling of cardiomyocytes. The impaired Ca2+ handling of cardiomyocytes isolated from NOS3KO mice subjected to CASP was associated with depressed mitochondrial ATP production, a determinant of the Ca2+ cycling capacity of sarcoplasmic reticulum (SR) Ca2+-ATPase. The NOS3-deficiency-induced impairment of the ability of mitochondria to produce ATP after CASP was at least in part attributable to reduction in mitochondrial respiratory chain complex I activity. These observations suggest that NOS3 protects against systemic inflammation and myocardial dysfunction after peritonitis-induced polymicrobial sepsis in mice.