title: The biological basis of malarial disease.
abstract: In this review we summarise the arguments that inflammatory cytokines, triggered by material released from the parasite at schizogony (malarial toxin), might induce the illness and pathology seen in malaria. These pro-inflammatory cytokines can generate inducible nitric oxide synthase and cause nitric oxide to be released, as can low concentrations of malarial toxin itself provided interferon-gamma, which has only low activity in the absence of malarial toxin, is present. We suggest here that recently described hypermetabolic functions of these mediators provide a much more plausible explanation for malarial hyperlactataemia and hypoglycaemia, the chief prognostic indicators in falciparum malaria, than does hypoxia secondary to mechanical blockage of vessels by sequestering parasites, which is the dominant current theory. We also review the arguments that rationalise, through these mediators, the reversibility of the coma of cerebral malaria. Although not yet tested at a cellular level, the proposal that nitric oxide generated in cerebral vascular walls contributes to this coma continues to gather indirect support. In addition, new evidence incriminating nitric oxide in the mechanism of tolerance to endotoxin rationalises the raised nitric oxide generation seen in malarial tolerance.
authors.affiliation: School of Life Sciences, Australian National University, Canberra, Australia. ian.clark@anu.edu.au
authors.forename: I A
authors.initials: IA
authors.lastname: Clark
authors.forename: F M
authors.initials: FM
authors.lastname: al Yaman
authors.forename: L S
authors.initials: LS
authors.lastname: Jacobson
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D016207:Cytokines / Q000502:physiology; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000502:physiology; D019344:Lactic Acid / Q000097:blood; D008288:Malaria / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D016779:Malaria, Cerebral / Q000209:etiology; D009569:Nitric Oxide / Q000502:physiology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D009569:Nitric Oxide; D019344:Lactic Acid