Inhaled Nitric Oxide and Cerebral Malaria: Basis of a Strategy for Buying Time for Pharmacotherapy

1Brigham and Women's Hospital, Harvard Medical School 2Institut de recherche pour le développement, France 3Epicentre Research Base, Mbarara, Uganda 4Mbarara University, Mbarara, Uganda 5Massachusetts General Hospital, Harvard Medical School.
The Pediatric Infectious Disease Journal (Impact Factor: 2.72). 07/2012; 31(12). DOI: 10.1097/INF.0b013e318266c113
Source: PubMed


There are approximately 225-600 million new malaria infections worldwide annually, with severe and cerebral malaria representing major causes of death internationally. The role of nitric oxide (NO) in the host response in cerebral malaria continues to be elucidated, with numerous known functions relating to the cytokine, endovascular, and cellular responses to infection with Plasmodium falciparum. Evidence from diverse modes of inquiry suggests NO to be critical in modulating the immune response and promoting survival in patients with cerebral malaria. This line of investigation has culminated in the approval of two phase II randomized prospective clinical trials in Uganda studying the use of inhaled NO as adjuvant therapy in children with severe malaria. The strategy underlying both trials is to use the sytemic anti-inflammatory properties of inhaled NO to "buy time" for chemical anti-parasite therapy to lower the parasite load. This paper reviews the nexus of malaria and nitric oxide biology with a primary focus on cerebral malaria in humans.

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Available from: Yap Boum II, Oct 09, 2015
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    • "In fact, it has been widely demonstrated that murine experimental cerebral malaria (ECM)-induced endothelial dysfunction depends on the adhesion of parasitized erythrocytes to cerebral microvasculature [4] [5] [6]; the production of inflammatory mediators, such as TNF-α, as well as increased expression of adhesion molecules on endothelial cells [7,8]. Recent advances concerning malaria treatment have suggested that an adjuvant therapy targeting endothelial activation improves patient outcome [9] [10] [11]. Indeed, prevention of BBB disruption has been shown to diminish ECM [3], which can be achieved via pharmacological induction of the stress-responsive protein heme oxigenase-1 (HO-1) and exposure to carbon monoxide, the end-product of HO-1 activity [12]. "
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    ABSTRACT: A breakdown of the brain–blood barrier (BBB) due to endothelial dysfunction is a primary feature of cerebral malaria (CM). Lipoxins (LX) are specialized pro-resolving mediators that attenuate endothelial dysfunction in different vascular beds. It has already been shown that LXA4 prolonged Plasmodium berghei-infected mice survival by a mechanism that depends on inhibiting IL-12 production and CD8+IFN-γ+ T cells in brain tissue; however, the effects of this treatment on endothelial dysfunction induced during experimental cerebral malaria (ECM) remains to be elucidated. Herein, we investigate the role of LXA4 on endothelial dysfunction during ECM. The treatment of P. berghei-infected mice with LXA4 prevented BBB breakdown and ameliorated behavioral symptoms but did not modulate TNF-α production. In addition, microcirculation analysis showed that treatment with LXA4 significantly increased functional capillary density in brains of P. berghei-infected C57BL/6 mice. Furthermore, histological analyses of brain sections demonstrated that exogenous LXA4 reduced capillary congestion that was accompanied by reduced ICAM-1 expression in the brain tissue. In agreement, LXA4 treatment of endothelial cells stimulated by Plasmodium berghei (Pb)- or Plasmodium falciparum (Pf)-parasitized red blood cells (RBCs) inhibited ICAM-1 expression. Additionally, LXA4 treatment restored the expression of HO-1 that is reduced during ECM. As well, LXA4 treatment inhibits PbRBC and PfRBC adhesion to endothelial cells that was reversed by the use of an HO-1 inhibitor (ZnPPIX). Our results demonstrate for the first time that LXA4 ameliorates endothelial dysfunction during ECM by modulating ICAM-1 and HO-1 expression in brain tissue.
    International Immunopharmacology 02/2015; 24(2):400-407. DOI:10.1016/j.intimp.2014.12.033 · 2.47 Impact Factor
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    • "Decreased Ang-1 or increased Ang-2 levels in serum, as measured by an increasing Ang-2/Ang-1 ratio, is associated with CM and can predict disease severity in adults and children (Conroy et al., 2009, 2010; Lovegrove et al., 2009; Jain et al., 2011; Prapansilp et al., 2013). Ang-1 and Ang-2 are regulated by nitric oxide, a signaling molecule in many processes, which is produced in the endothelium from L-arginine and causes vasorelaxation, vascular quiescence, down-regulation of endothelial adhesion molecules and reduces thrombosis (Bergmark et al., 2012). Nitric oxide bioavailability is reduced in SM and relates to fatal outcome and several groups have suggested that this could be linked to low L-arginine levels during malaria infection (Anstey et al., 1996; Lopansri et al., 2003; Yeo et al., 2007, 2008). "
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    ABSTRACT: Despite decades of research on cerebral malaria (CM) there is still a paucity of knowledge about what actual causes CM and why certain people develop it. Although sequestration of P. falciparum infected red blood cells has been linked to pathology, it is still not clear if this is directly or solely responsible for this clinical syndrome. Recent data have suggested that a combination of parasite variant types, mainly defined by the variant surface antigen, P. falciparum erythrocyte membrane protein 1 (PfEMP1), its receptors, coagulation and host endothelial cell activation (or inflammation) are equally important. This makes CM a multi-factorial disease and a challenge to unravel its causes to decrease its detrimental impact.
    Frontiers in Cellular and Infection Microbiology 07/2014; 4:100. DOI:10.3389/fcimb.2014.00100 · 3.72 Impact Factor
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    ABSTRACT: Macrophage phagocytosis is the first line of defense of the innate immune system against malaria parasite infection. This study evaluated the immunomodulatory effects of BCG and recombinant BCG (rBCG) strains expressing the C-terminus of the merozoite surface protein-1 (MSP-1C) of Plasmodium falciparum on mouse macrophage cell line J774A.1 in the presence or absence of lipopolysaccharide (LPS) or LPS + IFN-γ. The rBCG strain significantly enhanced phagocytic activity, production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nitric oxide (NO), and inducible nitric oxide synthase (iNOS) as compared with parental BCG strain, and these activities increased in the presence of LPS and LPS+IFN-γ. Furthermore, the rBCG strain also significantly reduced the macrophage viability as well as the rBCG growth suggesting the involvement of macrophage apoptosis. Taken together, these data indicate that the rBCG strain has an immunomodulatory effect on macrophages, thus strengthen the rational use of rBCG to control malaria infection.
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