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. 2011 Jan 21;404(3):877-81. doi: 10.1016/j.bbrc.2010.12.078. Epub 2010 Dec 22.
Excessive production of nitric oxide (NO) by NO synthase (NOS) and a subsequent oxidative stress reaction are thought to be critically involved in the pathophysiology of sepsis. Previous studies suggested that NO production by neuronal NOS (nNOS) and inducible NOS (iNOS) is implemented in the disease process at different time points after the injury. Here we tested the roles of selective pharmacological inhibition of nNOS and iNOS at different time points in a murine model of pulmonary sepsis. The injury was induced by intranasal administration of live Pseudomonas aeruginosa (3.2×10(7) colony-forming units) in C57BL/6 wild-type mice. The animals received no treatment (control) or treatment with a specific nNOS inhibitor (4 or 8h), iNOS inhibitor (4 or 8h), or non-specific NOS inhibitor (4 or 8h). In controls, the injury was associated with excessive releases of pro-inflammatory cytokines in the plasma, enhanced tissue lipid peroxidation, and decreased survival. Non-specific NOS inhibition at either time point did not influence survival and was not further investigated. While nNOS inhibition at 4h was associated with a trend toward improved survival and significantly reduced contents of lung nitrite/nitrate (NO(x)) and liver malondialdehyde, the blockade of nNOS at 8h had no effect on these parameters. In contrast, early iNOS inhibition was associated with a trend toward decreased survival and no effects on lung NO(x) and liver malondialdehyde contents, whereas later iNOS blockade was associated with decreased malondialdehyde content in liver homogenates. In conclusion, pulmonary sepsis in mice may be beneficially influenced by specific pharmacological nNOS inhibition at an earlier time point and iNOS inhibition at a later time points post-injury. Future investigations should identify the time changes of the expression and activation of NOS isoforms.
过量的一氧化氮（NO）由一氧化氮合酶（NOS）产生，随后发生氧化应激反应，被认为在脓毒症的病理生理学中起着关键作用。先前的研究表明，神经元型一氧化氮合酶（nNOS）和诱导型一氧化氮合酶（iNOS）产生的 NO 在损伤后不同时间点参与疾病过程。在这里，我们在肺部脓毒症的小鼠模型中测试了选择性抑制 nNOS 和 iNOS 在不同时间点的作用。损伤通过鼻腔内给予活的铜绿假单胞菌（3.2×10(7)个菌落形成单位）诱导 C57BL/6 野生型小鼠。动物未接受治疗（对照组）或接受特定的 nNOS 抑制剂（4 或 8 小时）、iNOS 抑制剂（4 或 8 小时）或非特异性 NOS 抑制剂（4 或 8 小时）治疗。在对照组中，损伤与血浆中促炎细胞因子的过度释放、组织脂质过氧化增强和存活率降低有关。非特异性 NOS 抑制在任何时间点均不影响存活率，因此不再进一步研究。虽然 nNOS 抑制在 4 小时与存活趋势改善相关，并且显著降低肺硝酸盐/亚硝酸盐（NO(x)）和肝丙二醛含量，但 8 小时阻断 nNOS 对这些参数没有影响。相反，早期 iNOS 抑制与存活率降低趋势相关，对肺 NO(x)和肝丙二醛含量无影响，而晚期 iNOS 阻断与肝匀浆丙二醛含量降低相关。总之，在损伤后早期进行特定的 nNOS 抑制和晚期进行 iNOS 抑制可能对小鼠肺部脓毒症产生有益影响。未来的研究应确定 NOS 同工型表达和激活的时间变化。
