Bradykinin contributes to vasogenic edema in murine experimental cerebral malaria.

Cerebral malaria (CM) from Plasmodium falciparum is a major cause of death in African children. Since bradykinin (BK) is a mediator of vasogenic edema, we hypothesized that it contributes to the pathogenesis of CM in Kenyan children and Plasmodium berghei ANKA-infected (PbA-infected) C57BL/6J mice in experimental CM (ECM). Cleaved plasma high-molecular-weight kininogen (cHK) is a marker for 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 with ECM had circulating cHK, elevated BK levels, and reduced HK and prekallikrein activity/antigen levels. HK-null (Kng1-/-), combined BK B1- and B2 receptor-null (Bdkrb1-/-Bdkrb2-/-), BK B2 receptor-null (Bdkrb2-/-), or BK B1 receptor-null (Bdkrb1-/-) mice were protected significantly from neurologic deterioration and brain edema compared with wild-type mice. F12-/- mice were not protected from neurological deterioration. Prekallikrein-null (Klkb1-/-), prolylcarboxypeptidase hypomorph (Prcpgt/gt), and brain endothelial cell conditional KO of PRCP (Prcpfl/fl Cre) mice with ECM had reduced neurologic deterioration and brain edema. Adjuvant plasma kallikrein inhibition combined with artesunate treatment in PbA-infected mice reversed neurologic deterioration and brain edema and significantly prolonged survival over artesunate alone. BK-induced vasogenic edema contributes to human and murine CM.