Deficiencies of carboxypeptidase N and carboxypeptidase B2 have opposite effects in a virulent mouse E. coli sepsis model.

Abstract

BACKGROUND: Two basic carboxypeptidases circulate in plasma, procarboxypeptidase B2, which is activated to carboxypeptidase B2 (CPB2), and carboxypeptidase N (CPN). These enzymes inactivate complement anaphylatoxins, C3a and C5a, with high C5a being toxic. OBJECTIVES: To test the hypothesis that these carboxypeptidases would affect Escherichia coli sepsis in mice differently because CPN is constitutively active while procarboxypeptidase B2 beeds to be locally activated. METHODS: Mice deficient in CPB2, CPN, or both enzymes were infected with E. coli and their health and survival was compared to wild-type mice. Clinical chemistry, complete blood count, and bacterial load were assessed. RESULTS: Lack of CPB2 prolonged survival while lack of CPN shortened survival compared to wild-type mice. Liver damage was higher in double deficient mice that were also thrombocytopenic, and CPN-deficient mice were leukopenic. Bacterial load was higher in CPB2 and double deficient mice and lower in CPN-deficient mice. CONCLUSION: CPN provides first-line protection against excessive C3a and C5a, accounting for the shortened survival in CPN-deficient mice in this sepsis model, despite reduced E. coli load. CPB2 serves a supportive role by primarily inactivating C3a locally. Apparently, CPB2 deficiency led to enhanced local levels of protective C3a and prolonged survival in the CPB2-deficient mice in this model, while the lack of CPN exacerbated the infection.