Papel do fator de ativação plaquetário (PAF) na malária experimental induzida por Plasmodium berghei cepa ANKA

Abstract

Platelet-activating factor (PAF) is an inflammatory mediator able to change vascular permeability and activate polymorphonuclear cells and monocytes, leading to actions with deleterious consequences for the host. Given its significance under inflammatory conditions, the aim of this study was to investigate the role of this molecule in experimentalcerebral malaria through the use of mice lacking the PAF receptor (PAFR-/-) and the administration of antagonists for this receptor. Animals PAFR-/- showed protective effect against infection when compared to C57Bl/6 WT, as evidenced by a significant delay in lethality. However, no differences in parasitemia and behavioral parameters were noticed.Histopathological analysis in brain tissue demonstrated that C57Bl/6 WT presented increased vascular obstruction and more severe cerebellar hemorrhage, in comparison with PAFR-/- mice (6dpi). The histopathological changes in the lungs of WT infected mice werealso more expressive when compared with PAFR-/- mice. On day 6p.i., WT and PAFR-/- mice presented a significant increase in leukocyte rolling and adhesion in brain endothelium compared to controls, as well as in the expression of adhesion molecules. Nevertheless, these events were similar between WT and PAFR-/- mice. The profile of cytokines and chemokines in brain tissue was not different between the two groups,although there were differences in systemic levels of these molecules, with higher concentration in C57Bl/6 WT infected mice. Caspase-3 activation was higher in brain of WT compared with PAFR-/- mice. Immunohistochemistry analysis of brain tissue revealed a greater intensity for cleaved caspase-3 in endothelial cells and sequestered leukocytes in WT infected mice. The evaluation of vascular permeability showed a stronger Evans blue extravasation into the brain and pulmonary parenchyma in WT infected mice in comparison to PAFR-/- mice. There was a significant increase in the recruitment and activation of CD8+T cells in the brain tissue of infected animals, whereas PAFR-/- mice exhibited a lower count of these parameters than WT animals. PAFR-/- infected mice also presented fewer macrophages and CD8+ T cells in lung when compared with C57Bl/6 mice. Treatment with PAFR antagonist, UK-74,505 in WT infected mice delayed lethality when compared to animals that received vehicle. This therapeutic strategy triggered a protection similar that was found in PAFR-/- infected mice, suggesting that PAFR signaling is important for the development of experimental cerebral malaria. Mechanistically, the activation of PAFR iscrucial for the cascade of events leading to changes in vascular permeability, recruitment and activation of CD8+ T cells, apoptosis of endothelial cells and leukocytes