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| Item Type: | Article |
|---|---|
| Title: | Bradykinin contributes to vasogenic edema in murine experimental cerebral malaria |
| Creators: |
de Sa Pinheiro, Alessandro S., Teixeira, Douglas E., Silva-Aguiar, Rodrigo P., Shim, Young Jun, Merkulova, Alona A., Silbak, Sadiq, Skomorovska-Prokvolit, Yelenna, Midem, David, Ogolla, Sidney, Burckhardt, Bjoern B., Gangnus, Tanja, Scharfstein, Julio, Caruso-Neves, Celso, McCarty, Owen Jt, Gailani, David, Bader, Michael  ORCID: https://orcid.org/0000-0003-4780-4164, Rosenthal, Philip J., Dent, Arlene E., Janse, Chris J., McCrae, Keith R., de Sa Pinheiro, Ana Acacia, Kazura, James W. and Schmaier, Alvin H.
|
| Abstract: | 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 (PbA) infected C57BL/6J mice in experimental cerebral malaria (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 (Bdkrb2(–/–)) or BK B1 (Bdkrb1(–/–)) receptor null mice were protected significantly 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 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. |
| Keywords: | Animal Disease Models, Bradykinin, Bradykinin B1 Receptor, Bradykinin B2 Receptor, Brain Edema, Cerebral Malaria, Inbred C57BL Mice, Kininogens, Knockout Mice, Plasmodium berghei |
| Source: | Journal of Clinical Investigation |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 136 |
| Number: | 17 |
| Page Range: | e202285 |
| Date: | 1 September 2026 |
| Official Publication: | https://doi.org/10.1172/jci202285 |
| PubMed: | View item in PubMed |
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