NITRIC-OXIDE IN TANZANIAN CHILDREN WITH MALARIA - INVERSE RELATIONSHIP BETWEEN MALARIA SEVERITY AND NITRIC-OXIDE PRODUCTION NITRIC-OXIDE SYNTHASE TYPE-2 EXPRESSION

Nitric oxide (NO)-related activity has been shown to be protective aga inst Plasmodium falciparum in vitro. It has been hypothesized, however , that excess NO production contributes to the pathogenesis of cerebra l malaria. The purpose of this study was to compare markers of NO prod uction [urinary and plasma nitrate + nitrate (NOx)], leukocytc-inducib le nitric oxide synthase type 2 (NOS2), and plasma TNF-alpha and IL-10 levels with disease severity in 191 Tanzanian children with and witho ut malaria. Urine NOx excretion and plasma NOx levels (corrected for r enal impairment) were inversely related to disease severity, with leve ls highest in subclinical infection and lowest in fatal cerebral malar ia. Result could not be explained by differences in dietary nitrate in gestion among the groups. Plasma levels of IL-10, a cytokine known to suppress NO synthesis, increased with disease severity. Leukocyte NOS2 antigen was detectable in all control children tested and ill all tho se with subclinical infection, but was undetectable in all but one sub ject with cerebral malaria. This suppression of NO synthesis in cerebr al malaria may contribute to pathogenesis. In contrast, high fasting N Ox levels and leukocyte NOS2 in healthy controls and asymptomatic infe ction suggest that increased NO synthesis might protect against clinic al disease. NO appears to have a protective rather than pathological r ole in African children with malaria.