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Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria.

Abstract：

: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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Gramaglia I,Sobolewski P,Meays D,Contreras R,Nolan JP,Frangos JA,Intaglietta M,van der Heyde HC

doi

10.1038/nm1499

subject

Has Abstract

pub_date

2006-12-01 00:00:00

pages

1417-22

issue

12

eissn

1078-8956

issn

1546-170X

pii

nm1499

journal_volume

12

pub_type

杂志文章

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