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(American Journal of Pathology. 2003;162:1651-1660.)
© 2003 American Society for Investigative Pathology

Anti-Adhesive Effect of Nitric Oxide on Plasmodium falciparum Cytoadherence under Flow

Supattra Serirom^*, Wahaju H. Raharjo^*, Kesinee Chotivanich, Sornchai Loareesuwan, Paul Kubes^* and May Ho^*

From the Department of Microbiology and Infectious Diseases and Immunology Research Group,^* University of Calgary, Calgary, Alberta, Canada; and the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

Nitric oxide (NO) is widely known to inhibit platelet and leukocyte adhesion to endothelium through its regulatory effect on adhesion molecule expression. The objective of the present study was to investigate if NO affects the cytoadherence of Plasmodium falciparum-infected erythrocytes (IRBCs) to human microvascular endothelium (HDMECs) under flow conditions in vitro. The effect of endogenous NO was studied using the NO synthase inhibitor L-N^G-nitro-arginine-methyl-ester (L-NAME). Treatment of HDMECs with 3 mmol/L of L-NAME for 4 hours significantly enhanced IRBC adhesion and the effect could be reversed by an anti-P-selectin but not an anti-VCAM-1 antibody. The effect of exogenous NO on cytoadherence was studied by using the NO donor 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (PPN). PPN (300 µmol/L) treatment reduced the number of adherent IRBCs on resting HDMECs by down-regulating basal ICAM-1 expression, and on tumor necrosis factor--stimulated HDMECs by inhibition of VCAM-1 induction and down-regulation of ICAM-1 expression. The inhibitory effect of PPN on tumor necrosis factor--induced VCAM-1 expression at 24 hours was evident when the NO donor was added for as short as 2 hours. These findings suggest that NO may be protective against P. falciparum infection by inhibiting cytoadherence, and underscore the therapeutic potential of NO in the treatment of severe falciparum malaria.

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