Activation mechanism of human Hageman factor-plasma kallikreinkinin system by Vibrio vulnificus metalloprotease

Vibro vulnificus, an opportunistic human pathogen, secretes a metalloprotease (VVP). The VVP inoculated into a guinea pig is known to generate bradykinin through activation of the Hageman factor-plasma kallikrein-kinin system. VVP was shown to poisess the ability to activate the human system through the same mechanism as that clarified in the guinea pig system, namely, VVP converted both human zymogens (Hageman factor and plasma prekallikrein) to active enzymes (activated Hageman factor and plasma kallikrein), and the then generated kallikrein liberated bradykinin from high molecular-weight kininogen. However, in the presence of plasma α₂-macroglobulin (α₂M), the VVP action was drastically decreased. This finding suggests that the human system might be activated only at the interstitial-tissue space which contains negligible amounts of α₂M or in the bloodstream of the individuals whom plasma α₂M level is extremely reduced.