Figure 3.

Animal models of parasite infection and the role of kinins. (A) Leishmania promastigotes induced macrophage effector responses through B₂ receptor activation by BK in the paw edema model. The treatment with BK increased the uptake of promastigotes by macrophages, whereas HOE-140 blocked this effect. Even with the reduction of parasite internalization, the treatment with HOE-140 caused an increase in the rate of growth of intracellular amastigotes, making host cells susceptible to infection. (B) Trypomastigotes release kinins and sensitize dendritic cells (DCs) via B₂ receptor activation. A cooperative activation of TLR2, CXCR2 and B2 receptors induces type 1 immunity. An impairment of type-1 responses was observed in CD11c+ DCs isolated from spleen of B₂ receptor knockout mice, that had been infected by trypomastigotes, with reduced IL-12 production. (C) Monkeys or mice infected by Plasmodium presented decreased HMWK and LMWK levels, while serum kallikrein concentrations and kinin formation were elevated. These results were accompanied by increased parasitemia and kininase activity. Parasites internalized plasmatic kininogen and liberated vasoactive kinins (Lys-BK, BK, and des-Arg⁹-BK) through the activation of cysteine proteases falcipain-2 and falcipain-3. B₁ and B₂ receptor activation triggered intracellular Ca²⁺ increase in endothelial cells causing circulatory disturbances, while the selective kinin antagonists des-Arg⁹[Leu⁸]-BK and HOE-140 restored this effect. (D) Intradermal injection of Schistosoma cercariae into the guinea pig skin induced edema formation, BK release and leukocyte accumulation, while HOE-140 decreased the edema response. Adult male worms cleave HMWK through protease activation. Proteases trigger BK production from kininogen, stimulating the release of tissue plasminogen activator (tPA) from vascular endothelial cells, which would promote fibrinolysis and anticoagulant effects.