Hemostasis and Vascular Inflammation

Leung, Lawrence L.K.; Morser, John

doi:10.1002/9781118355244.ch10

Cited by 1 publication

(1 citation statement)

References 29 publications

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“…Removal of C‐terminal arginine residues from BK, C3a, and C5a inactivates them. Generally, CPB2 substrates promote inflammation, while the CPB2 cleavage products have lower inflammatory activity, suggesting that activation of pro‐CPB2 by the thrombin/TM complex, along with activation of protein C (PC), represents a homeostatic mechanism to regulate thrombin's inflammatory activity .…”

Section: Introductionmentioning

confidence: 99%

Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model

Shao

Nishimura

Leung

et al. 2015

Journal of Thrombosis and Haemostasis

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Summary Background and Objectives 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 proCPB2 was induced by CLP leading to increase in proCPB2 levels. Thrombomodulin present on mesothelium supported thrombin activation of proCPB2. Both WT 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 still retained their survival advantage. Administration of a C3a receptor antagonist exacerbated the disease in both WT 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 Thus 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.

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Section: Introductionmentioning

confidence: 99%