Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria
Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria
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DOI：
10.1038/nm1499
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发表时间：
2006-12-01
期刊：
影响因子：
82.9
通讯作者：
van der Heyde, Henri C.
中科院分区：
文献类型：
--
作者：
Gramaglia, Irene;Sobolewski, Peter;van der Heyde, Henri C.
一氧化氮（NO）在脑型疟疾发生中的作用是有争议的。大多数研究者提出，为杀死疟原虫而产生的高浓度NO的不幸后果是脑型疟疾的发展。在这里，我们已经测试了这种高NO生物利用度的假设，在实验性脑型疟疾（ECM）的设置，但发现相反，低NO生物利用度有助于ECM的发生。具体而言，小鼠血管NO合酶缺乏显示寄生虫血症和死亡率类似于对照小鼠中观察到的。外源性NO并不影响寄生虫血症，但提供了显着的保护ECM，事实上，外源性NO治疗的小鼠在临床上与未感染的小鼠在一个阶段时，控制感染的小鼠濒死。外源性NO的施用恢复了脑中NO介导的信号传导，降低了血液中的促炎生物标志物，并显著减少了血管渗漏和脑内点状出血。ECM过程中血管系统中NO生物利用度低，部分原因是血液中NO清除游离血红蛋白的增加，低维生素B2血症，以及血液和红细胞亚硝酸盐浓度低。外源性NO灭活血浆中清除NO的游离血红蛋白，并将亚硝酸盐恢复到未感染小鼠中观察到的浓度。因此，我们得出结论，低而不是高NO生物利用度有助于ECM的发生。
The role of nitric oxide ( NO) in the genesis of cerebral malaria is controversial. Most investigators propose that the unfortunate consequence of the high concentrations of NO produced to kill the parasite is the development of cerebral malaria. Here we have tested this high NO bioavailability hypothesis in the setting of experimental cerebral malaria (ECM), but find instead that low NO bioavailability contributes to the genesis of ECM. Specifically, mice deficient in vascular NO synthase showed parasitemia and mortality similar to that observed in control mice. Exogenous NO did not affect parasitemia but provided marked protection against ECM; in fact, mice treated with exogenous NO were clinically indistinguishable from uninfected mice at a stage when control infected mice were moribund. Administration of exogenous NO restored NO-mediated signaling in the brain, decreased proinflammatory biomarkers in the blood, and markedly reduced vascular leak and petechial hemorrhage into the brain. Low NO bioavailability in the vasculature during ECM was caused in part by an increase in NO-scavenging free hemoglobin in the blood, by hypoargininemia, and by low blood and erythrocyte nitrite concentrations. Exogenous NO inactivated NO-scavenging free hemoglobin in the plasma and restored nitrite to concentrations observed in uninfected mice. We therefore conclude that low rather than high NO bioavailability contributes to the genesis of ECM.