title: Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model.
abstract: OBJECTIVE
  Carboxypeptidase B2 (CPB2) is a basic carboxypeptidase with fibrin and complement C3a and C5a as physiological substrates. We hypothesized that in polymicrobial sepsis, CPB2-deficient mice would have sustained C5a activity, leading to disease exacerbation.
  
  
  METHODS
  Polymicrobial sepsis was induced by cecal ligation and puncture (CLP).
  
  
  RESULTS
  Contrary to our hypothesis, Cpb2(-/-) mice had significantly improved survival, with reduced lung edema, less liver and kidney damage, and less disseminated intravascular coagulation. Hepatic pro-CPB2 was induced by CLP, leading to increased pro-CPB2 levels. Thrombomodulin present on mesothelium supported thrombin activation of pro-CPB2. Both wild-type and Cpb2(-/-) animals treated with a C5a receptor antagonist had improved survival, demonstrating that C5a was detrimental in this model. Treatment with a fibrinolysis inhibitor, tranexamic acid, caused a decrease in survival in both genotypes; however, the Cpb2(-/-) animals retained their survival advantage. Administration of a C3a receptor antagonist exacerbated the disease in both wild-type and Cpb2(-/-) mice and eliminated the survival advantage of Cpb2(-/-) mice. C5a receptor is expressed in both peritoneal macrophages and neutrophils; in contrast, C3a receptor expression is restricted to peritoneal macrophages, and C3a induced signaling in macrophages but not neutrophils.
  
  
  CONCLUSIONS
  While C5a exacerbates the peritonitis, resulting in a deleterious generalized inflammatory state, C3a activation of peritoneal macrophages may limit the initial infection following CLP, thereby playing a diametrically opposing protective role in this polymicrobial sepsis model.
authors: Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.|Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors: Z
authors: Z
authors: Shao
authors: Department of Anesthesiology, Stanford University School of Medicine, Stanford, CA, USA.
authors: T
authors: T
authors: Nishimura
authors: Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.|Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors: L L K
authors: LL
authors: Leung
authors: Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.|Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors: J
authors: J
authors: Morser
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001778:Blood Coagulation Disorders / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D025901:Carboxypeptidase B2 / Q000172:deficiency* / Q000235:genetics; D002432:Cecum / Q000382:microbiology / Q000601:surgery; D002478:Cells, Cultured; D015926:Complement C3a / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005337:Fibrin / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D007970:Leukopenia / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D008026:Ligation; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D065840:Protective Factors; D011677:Punctures; D012307:Risk Factors; D018805:Sepsis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000378:metabolism; D013997:Time Factors
chemical_list: D000933:Antifibrinolytic Agents; D018836:Inflammation Mediators; C569169:THBD protein, mouse; D018180:Thrombomodulin; D015926:Complement C3a; D015936:Complement C5a; D005337:Fibrin; D025901:Carboxypeptidase B2; C585365:Cpb2 protein, mouse; D013917:Thrombin
keywords: anaphylatoxin; carboxypeptidase B2; fibrinolysis; inflammation; sepsis