Bradykinin Contributes to Vasogenic Edema in Murine Experimental Cerebral Malaria.

Cerebral malaria (CM) due to Plasmodium falciparum ( Pf ) infection is a major cause of death in African children. Bradykinin (BK) is a mediator of vasogenic edema. It could contribute to the pathogenesis of central nervous system malaria in Kenyan children and P. berghei ANKA ( PbA ) infected C57BL/6J mice with experimental cerebral malaria. Cleaved plasma high molecular weight kininogen (cHK) is a marker for prior BK release. 40% of children with central nervous system malaria had plasma cHK versus 18% of children with uncomplicated malaria. Wild-type PbA -infected mice had circulating plasma cHK, elevated BK levels, and reduced HK and prekallikrein levels. HK null ( Kng1 -/- ), combined BK B1 and B2 receptor null ( Bdkrb1 -/- / Bdkrb2 -/- ), BK B2 ( Bdkrb2 -/- ) or BK B1 ( Bdkrb1 -/- ) receptor null mice were protected from neurologic deterioration and brain edema compared to wild-type mice. F12 -/- mice were not protected from neurological deterioration. Prekallikrein null ( Klkb1 -/- ), prolylcarboxypeptidase hypomorphs ( Prcp gt/gt ), and brain endothelial cell conditional knockout of PRCP ( Prcp fl/fl Cre) mice had reduced neurologic deterioration and brain edema. Adjuvant plasma kallikrein inhibition combined with artesunate treatment of PbA -infected mice reversed neurologic deterioration and brain edema and prolonged survival relative to artesunate alone. BK-induced vasogenic edema contributes to human and murine CM.