Carboxypeptidase B2 and N play different roles in regulation of activated complements C3a and C5a in mice.

Autor: Morser J; Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA., Shao Z; Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA., Nishimura T; Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA., Zhou Q; Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA., Zhao L; Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA., Higgins J; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Leung LLK; Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.
Jazyk: angličtina
Zdroj: Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2018 May; Vol. 16 (5), pp. 991-1002. Date of Electronic Publication: 2018 Apr 06.
DOI: 10.1111/jth.13964
Abstrakt: Essentials Two basic carboxypeptidases are present in plasma, B2 (CPB2) and N (CPN). Cpb2 -/- and Cpn -/- mice were challenged in a hemolytic uremic syndrome (HUS) model vs. wild type. Cpb2 -/- exacerbates HUS while Cpn -/- exacerbates cobra venom factor challenge vs. wild type mice. CPB2 and CPN have overlapping but non-redundant roles.
Summary: Background There are two basic carboxypeptidases in plasma. Carboxypeptidase B2 (CPB2) is activated from a circulating zymogen, proCPB2, and carboxypeptidase N (CPN) is constitutively active with both inactivating complement C3a and C5a. Aims To test the roles of CPB2 and CPN in complement-driven mouse models of cobra venom factor (CVF) challenge and hemolytic-uremic syndrome (HUS). Methods Cpb2 -/- , Cpn -/- and wild-type (WT) mice were compared in an HUS model induced by Shiga toxin and lipopolysaccharide administration and following CVF administration. Results HUS was exacerbated in Cpb2 -/- mice more than in Cpn -/- mice, compared with WT mice. Cpb2 -/- mice developed the HUS clinical triad of microangiopathic hemolytic anemia, uremia and thrombocytopenia. Treatment with anti-C5 antibody improved survival of both Cpb2 -/- and Cpn -/- mice. In contrast, when challenged acutely with CVF, the reverse phenotype was observed. Cpn -/- mice had markedly worse disease than Cpb2 -/- mice, whereas the WT mice were resistant. Conclusions CPN and CPB2 play overlapping but non-redundant roles in regulating complement activation in vivo. The constitutively active CPN is key for inactivation of systemic C5a, whereas CPB2 functions as an on-demand supplementary anaphylatoxin inhibitor in inactivating excessive C5a formed locally.
(© 2018 International Society on Thrombosis and Haemostasis.)
Databáze: MEDLINE
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