Abstract

BACKGROUND: Kallikrein is generated when the contact system is activated, subsequently cleaving high molecular weight kininogen to bradykinin (BK). BK binds to bradykinin receptor 2 (B2R) causing vascular leakage. BK is inactivated by proteolysis by the plasma carboxypeptidase B2 and N (CPB2 and CPN). CPN is constitutively active but CPB2 is generated from its zymogen, proCPB2.OBJECTIVES: Determine the role of CPB2 and CPN in the regulation of vascular leakage.METHODS: Mice deficient in CPB2, CPN or both (Cpb2-/- , Cpn-/- and Cpb2-/- /Cpn-/- ) were compared to wild type mice (WT) in a model of vascular leakage caused by skin irritation. In some experiments mice were pretreated with antibodies that prevent activation of proCPB2.RESULTS: Skin irritation increased vascular leakage most in Cpb2-/- /Cpn-/- , less in Cpb2-/- and Cpn-/- and least in WT mice. There was no difference in vascular leakage without the challenge. Antibodies inhibiting activation of proCPB2 by plasmin, but not by the thrombin/thrombomodulin (TM) complex, increased vascular leakage to the level seen in Cpb2-/- mice. There was no change in levels of markers of coagulation and fibrinolysis.CONCLUSIONS: BK is inactivated by both CPB2 and CPN independently. Plasmin is the activator of proCPB2 in this model. Mice lacking both plasma carboxypeptidases have more vascular leak than ones lacking either alone. Although BK levels were not determined, BK is the likely substrate for CPB2 and CPN in this model.

View details for DOI 10.1111/jth.15551

View details for PubMedID 34626062