Department of Anesthesiology, Investigational Intensive Care Unit, The University of Texas Medical Branch and Shriners Hospitals for Children, Galveston, TX 77550, USA.
Biochem Biophys Res Commun. 2010 Aug 20;399(2):286-91. doi: 10.1016/j.bbrc.2010.07.071. Epub 2010 Jul 22.
Excessive production of nitric oxide (NO) by NO synthase (NOS) with subsequent formation of peroxynitrite and poly(adenosine diphosphate ribose) is critically implemented in the pathophysiology of acute lung injury and sepsis. To elucidate the roles of different isoforms of NOS, we tested the effects of non-selective NOS inhibition and neuronal NOS (nNOS)- and inducible NOS (iNOS)-gene deficiency on the pulmonary oxidative and nitrosative stress reaction in a murine sepsis model. The injury was induced by four sets of cotton smoke using an inhalation chamber and subsequent intranasal administration of live Pseudomonas aeruginosa (3.2x10(7) colony-forming units). In wild type mice, the injury was associated with excessive releases of pro-inflammatory cytokines in the plasma, enhanced neutrophil accumulation, increased lipid peroxidation, and excessive formation of reactive nitrogen species and vascular endothelial growth factor in the lung. Both nNOS- and iNOS-gene deficiency led to significantly reduced oxidative and nitrosative stress markers in the lung, but failed to significantly improve survival. Treatment with a non-selective NOS inhibitor failed to reduce the oxidative and nitrosative stress reaction to the same extent and even tended to increase mortality. In conclusion, the current study demonstrates that both nNOS and iNOS are partially responsible for the pulmonary oxidative and nitrosative stress reaction in this model. Future studies should investigate the effects of specific pharmacological inhibition of nNOS and iNOS at different time points during the disease process.
一氧化氮合酶（NOS）过度产生一氧化氮（NO），随后形成过氧亚硝酸盐和多（腺苷二磷酸核糖），这在急性肺损伤和败血症的病理生理学中起着关键作用。为了阐明不同 NOS 同工型的作用，我们测试了非选择性 NOS 抑制以及神经元 NOS（nNOS）和诱导型 NOS（iNOS）基因缺失对小鼠败血症模型中肺氧化和硝化应激反应的影响。损伤是通过在吸入室中使用四组棉花烟雾并用活铜绿假单胞菌（3.2x10(7)个菌落形成单位）进行鼻内给药来诱导的。在野生型小鼠中，损伤与血浆中促炎细胞因子的过度释放、中性粒细胞积聚增加、脂质过氧化增加以及肺中活性氮物种和血管内皮生长因子的过度形成有关。nNOS 和 iNOS 基因缺失均导致肺中氧化和硝化应激标志物显著降低，但未能显著提高生存率。非选择性 NOS 抑制剂的治疗未能在相同程度上减轻氧化和硝化应激反应，甚至有增加死亡率的趋势。总之，本研究表明，nNOS 和 iNOS 在该模型中均部分负责肺的氧化和硝化应激反应。未来的研究应在疾病过程的不同时间点研究特异性抑制 nNOS 和 iNOS 的药理学效果。
