Role of eicosanoids in the pathogenesis of murine cerebral malaria.

Abstract

Abstract. Because microvascular damage is a common feature of cerebral malaria, we have examined the role eicosanoid metabolites (prostaglandins and leukotrienes) in experimental cerebral malaria. Eighty ICR mice were infected with Plasmodium berghei ANKA, with 40 uninfected mice as controls. Half of the infected mice were treated on days 4 and 5 with aspirin, a prostaglandin synthesis inhibitor. Infected mice started to die of cerebral malaria on day 6, and by day 17, all infected mice died. In contrast, all infected mice treated with aspirin died by day 12. Infected mice had increased phospholipase A2 mRNA expression in the spleen and cyclooxygenase 1 (COX1) and COX2 expression in the brain. At the peak of cerebral malaria, infected mice had higher serum leukotriene B4 levels than control mice, and aspirin-treated infected mice had higher serum leukotriene B4 levels than untreated infected mice. These results suggest that prostaglandins are protective whereas leukotrienes are detrimental in cerebral malaria.Microvascular damage is a common feature of both primate and murine cerebral malaria. Humans who die of cerebral malaria caused by Plasmodium falciparum infection have petechial and ring hemorrhage and edema in the brain. [1][2][3][4][5][6] Similar findings are also seen in cerebral malaria of rhesus monkeys caused by P. coatneyi 7 and of mice caused by P. berghei ANKA. 8 The mechanisms involved in the induction of microvascular damage during cerebral malaria are not well studied. Because cerebral malaria is associated with the over-production of T helper-1 and proinflammatory cytokines (tumor necrosis factor-␣ [tnF-␣], interferon-␥ [IFN-␥], and interleukin-1 [IL-1]), 9-11 it is suggested that these cytokines cause cerebral malaria by up-regulation of intercellular adhesion molecule-1 (a cytoadhesion molecule involved in the adhesion of parasitized erythrocytes and mononuclear cells to endothelial cells) expression and nitric oxide production, which lead to mechanic blockage and disrupted neurotransmission. 11-13 However, whether endothelial blockage and activation themselves cause brain hemorrhage is not clear. The role of platelets in cerebral malaria has attracted some attention, although detailed pathways for the plateletinduced pathology have not yet been studied. 14 An alternative effect of the proinflammatory cytokines is the modulation on the production of eicosanoids (prostaglandins and leukotrienes), which are important in the maintenance of the structure and function of blood vessels. 15 Increased phospholipase A2 activities have been reported in adults infected with P. falciparum. 16 Children with cerebral malaria also have higher phospholipase A2 expression than those with uncomplicated malaria. 17 Because the expression of other enzymes such as cyclooxygenase 1 and 2 (COX1 and COX2) (for prostaglandin synthesis) and lipoxygenase (for leukotriene synthesis) in malaria infection is not known, it is not clear which eicosanoid pathway is involved in the pathogenesis. Malaria infection is known to ...

Suppression of Prostaglandin E2by Malaria Parasite Products and Antipyretics Promotes Overproduction of Tumor Necrosis Factor–α: Association with the Pathogenesis of Childhood Malarial Anemia

“…Previous reports showed that salicylate-derived antipyretics are commonly overused by caregivers and that they result in toxicity that can exacerbate severe cases of malaria [42]. Additional investigations of murine models of CM demonstrate that treatment with aspirin (a COX-1-selective inhibitor) and celecoxib (a COX-2-selective inhibitor) increase mortality and the early onset of CM, respectively [43,44]. Although the beneficial versus detrimental effects of antipyretic use during childhood malaria are largely unsubstantiated, previous case-control studies [45,46] illustrate that antipyretics, such as acetaminophen and naproxen, do not significantly reduce malarial fever, compared with mechanical fever-control measures (i.e., manual fanning) currently recommended by the World Health Organization [47].…”

Leukotrienes enhance the bactericidal activity of alveolar macrophages against Klebsiella pneumoniae through the activation of NADPH oxidase

“…Subsequently, numerous in vitro and in vivo models have revealed key roles for LTs in augmenting monocyte/macrophage phagocytosis [9][10][11][12] and microbicidal activity. 7,8,[11][12][13][14][15][16][17][18][19][20] With respect to pulmonary innate immunity, 5-LOdeficient mice demonstrated impaired bacterial clearance and enhanced mortality during pneumonia caused by Klebsiella pneumoniae. 11 In vitro, endogenous and exogenous LTs enhanced Fc␥-receptor-mediated phagocytosis by the AMs.…”

Impaired Systemic Production of Prostaglandin E2in Children with Cerebral Malaria

“…Although measurement of PGE 2 and COX-2 gene expression in those studies was performed before treatment with antimalarials and/or antipyretics, previous studies of Gabonese children within the same geographic region have shown that treatment of malaria-infected children with acetaminophen (paracetamol) is associated with adverse outcomes, such as prolonged time to clearance of parasites and decreased production of TNF-a and oxygen radicals [14]. Studies using murine models of CM have shown that blockade of formation of PGs, by aspirin, is associated with increased mortality [15] and that more-selective inhibition of COX-2 by celecoxib is associated with an earlier onset of CM [16]. Taken together, the findings of these studies suggest that enhanced production of PGE 2 is associated with protective effects and that reduced levels of PGE 2 may promote increased pathogenesis.…”