Endothelial nitric oxide synthase inhibition triggers inflammatory responses in the brain of male rats exposed to ischemia-reperfusion injury
Endothelial nitric oxide synthase inhibition triggers inflammatory responses in the brain of male rats exposed to ischemia-reperfusion injury
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DOI：
10.1002/jnr.24101
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发表时间：
2018-01-01
影响因子：
4.2
通讯作者：
Tassorelli, Cristina
中科院分区：
文献类型：
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作者：
Greco, Rosaria;Demartini, Chiara;Tassorelli, Cristina
一氧化氮（NO）来源于内皮型一氧化氮合酶（eNOS），在保护和维持脑微循环、抑制血小板聚集、白细胞粘附和迁移中起作用。eNOS活性的抑制通过触发不同的细胞机制（包括炎症反应）导致缺血后神经元损伤的加重。为了检查eNOS在中风诱导的神经炎症中的相对贡献，我们分析了用l-N-脱氧核糖核酸系统治疗的效果。（1-亚氨基乙基）鸟氨酸（L-NIO），一种相对选择性的eNOS抑制剂，对天然免疫调节和内皮功能障碍的关键介质MiR-155- 5 p表达的影响，短暂大脑中动脉闭塞（tMCAo）后再灌注24小时的雄性大鼠皮质中的诱导型一氧化氮合酶（iNOS）和白细胞介素-10（IL-10）mRNA的表达进行了评价，通过实时聚合酶链反应在皮质匀浆和居民和浸润免疫细胞分离缺血皮质。还分析了这些后一种细胞的CD 40表达，CD 40是小胶质细胞/巨噬细胞M1极化的标志物。与假手术相比，tMCAo在缺血皮质中产生了miR 155 - 5 p和iNOS表达的显著升高。eNOS抑制L-NIO治疗进一步提高了这些炎症介质的皮质表达，而不影响IL-10 mRNA水平。有趣的是，iNOS的调节发生在缺血半球的常驻和浸润免疫细胞中。因此，与注射载体的动物相比，L-NIO诱导缺血皮质的CD 68（+）小胶质细胞/巨噬细胞中的CD 40（+）事件的百分比显著增加。这些发现表明，炎症反应可能是脑缺血中eNOS药理学抑制的有害作用的基础。
Nitric oxide (NO) derived from endothelial NO synthase (eNOS) plays a role in preserving and maintaining the brain's microcirculation, inhibiting platelet aggregation, leukocyte adhesion, and migration. Inhibition of eNOS activity results in exacerbation of neuronal injury after ischemia by triggering diverse cellular mechanisms, including inflammatory responses. To examine the relative contribution of eNOS in stroke-induced neuroinflammation, we analyzed the effects of systemic treatment with l-N-(1-iminoethyl)ornithine (L-NIO), a relatively selective eNOS inhibitor, on the expression of MiR-155-5p, a key mediator of innate immunity regulation and endothelial dysfunction, in the cortex of male rats subjected to transient middle cerebral artery occlusion (tMCAo) followed by 24hr of reperfusion. Inducible NO synthase (iNOS) and interleukin-10 (IL-10) mRNA expression were evaluated by real-time polymerase chain reaction in cortical homogenates and in resident and infiltrating immune cells isolated from ischemic cortex. These latter cells were also analyzed for their expression of CD40, a marker of M1 polarization of microglia/macrophages.tMCAo produced a significant elevation of miR155-5p and iNOS expression in the ischemic cortex as compared with sham surgery. eNOS inhibition by L-NIO treatment further elevated the cortical expression of these inflammatory mediators, while not affecting IL-10 mRNA levels. Interestingly, modulation of iNOS occurred in resident and infiltrating immune cells of the ischemic hemisphere. Accordingly, L-NIO induced a significant increase in the percentage of CD40(+) events in CD68(+) microglia/macrophages of the ischemic cortex as compared with vehicle-injected animals. These findings demonstrate that inflammatory responses may underlie the detrimental effects due to pharmacological inhibition of eNOS in cerebral ischemia.