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Inhaled nitric oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria.

TitleInhaled nitric oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria.
Publication TypeJournal Article
Year of Publication2011
AuthorsSerghides, L, Kim, H, Lu, Z, Kain, DC, Miller, C, Francis, RC, W Liles, C, Zapol, WM, Kain, KC
JournalPLoS One
Volume6
Issue11
Paginatione27714
Date Published2011
ISSN1932-6203
KeywordsAdministration, Inhalation, Animals, Artemisinins, Blood Vessels, Blood-Brain Barrier, Brain, Endothelial Cells, Gene Expression Regulation, Inflammation, Intercellular Adhesion Molecule-1, Malaria, Cerebral, Male, Mice, Nitric Oxide, Plasmodium berghei, Survival Analysis, Time Factors
Abstract

The host immune response contributes to the onset and progression of severe malaria syndromes, such as cerebral malaria. Adjunctive immunomodulatory strategies for severe malaria may improve clinical outcome beyond that achievable with artemisinin-based therapy alone. Here, we report that prophylaxis with inhaled nitric oxide significantly reduced systemic inflammation (lower TNF, IFNγ and MCP-1 in peripheral blood) and endothelial activation (decreased sICAM-1 and vWF, and increased angiopoeitin-1 levels in peripheral blood) in an experimental cerebral malaria model. Mice that received inhaled nitric oxide starting prior to infection had reduced parasitized erythrocyte accumulation in the brain, decreased brain expression of ICAM-1, and preserved vascular integrity compared to control mice.Inhaled nitric oxide administered in combination with artesunate, starting as late as 5.5 days post-infection, improved survival over treatment with artesunate alone (70% survival in the artesunate only vs. 100% survival in the artesunate plus iNO group, p = 0.03). These data support the clinical investigation of inhaled nitric oxide as a novel adjunctive therapy in patients with severe malaria.

DOI10.1371/journal.pone.0027714
Alternate JournalPLoS ONE
PubMed ID22110737