title: Inhaled nitric oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria.
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.
authors: SA Rotman Laboratories, McLaughlin-Rotman Centre for Global Health, Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University Health Network-Toronto General Hospital, and University of Toronto, Toronto, Canada.
authors: Lena
authors: L
authors: Serghides
authors: Hani
authors: H
authors: Kim
authors: Ziyue
authors: Z
authors: Lu
authors: Dylan C
authors: DC
authors: Kain
authors: Chris
authors: C
authors: Miller
authors: Roland C
authors: RC
authors: Francis
authors: W Conrad
authors: WC
authors: Liles
authors: Warren M
authors: WM
authors: Zapol
authors: Kevin C
authors: KC
authors: Kain
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D001808:Blood Vessels / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D010962:Plasmodium berghei / Q000472:pathogenicity; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D037621:Artemisinins; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D000077332:Artesunate