Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice

Abstract

Thrombin-activatable fibrinolysis inhibitor (TAFI), also known as carboxypeptidase R, has been implicated as an important negative regulator of the fibrinolytic system. In addition, TAFI is able to inactivate inflammatory peptides such as complement factors C3a and C5a. To determine the role of TAFI in the hemostatic and innate immune response to abdominal sepsis, TAFI gene-deficient (TAFI−/−) and normal wild-type mice received an i.p. injection with Escherichia coli. Liver TAFI mRNA and TAFI protein concentrations increased during sepsis. In contrast to the presumptive role of TAFI as a natural inhibitor of fibrinolysis, TAFI−/− mice did not show any difference in E. coli-induced activation of coagulation or fibrinolysis, as measured by plasma levels of thrombin-anti-thrombin complexes and D-dimer and the extent of fibrin depositions in lung and liver tissues. However, TAFI−/− mice were protected from liver necrosis as indicated by histopathology and clinical chemistry. Furthermore, TAFI−/− mice displayed an altered immune response to sepsis, as indicated by an increased neutrophil recruitment to the peritoneal cavity and a transiently increased bacterial outgrowth together with higher plasma TNF-α and IL-6 levels. These data argue against an important part for TAFI in the regulation of the procoagulant-fibrinolytic balance in sepsis and reveals a thus far unknown role of TAFI in the occurrence of hepatic necrosis.

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

“…30 In a recently published Escherichia coli-induced peritonitis model in proCPB Ϫ/Ϫ mice, there was no evidence of perturbed fibrinolysis, as measured by D-dimer levels in plasma or the extents of fibrin deposition in lung and liver tissues. 31 Thus, the role of CPB as a fibrinolysis inhibitor in mice does not appear to be as significant as that in humans.…”

“…31 Studies have shown that C3a and C5a are capable of priming hepatocytes for regeneration, which is mediated by C3a and C5a binding to the C3aR and C5aR on Kupfer cells, a role distinct from the usual inflammatory role ascribed to C3a and C5a. 33,34 The result is consistent with the interpretation that there is more local C5a generation in the liver in the proCPB Ϫ/Ϫ mice in the peritonitis model, thus leading to enhanced liver regeneration and reduced liver necrosis.…”

“…30 In a recently published Escherichia coli-induced peritonitis model in proCPB Ϫ/Ϫ mice, there was no evidence of perturbed fibrinolysis, as measured by D-dimer levels in plasma or the extents of fibrin deposition in lung and liver tissues. 31 Thus, the role of CPB as a fibrinolysis inhibitor in mice does not appear to be as significant as that in humans.It is unlikely that the enhanced C5a-induced alveolitis observed in proCPB Ϫ/Ϫ mice in our study was due to perturbation in fibrinolysis. With proCPB deficiency, one would expect enhanced fibrinolysis and thus less fibrin deposition in the alveoli following C5a-induced inflammation.…”

Oxidized Phospholipids Inhibit Phagocytosis and Impair Outcome in Gram-Negative Sepsis In Vivo

“…Peritonitis was induced as described previously (9,23,24). In brief, E. coli O18:K1 was cultured in Luria-Bertani medium (Difco) at 37°C, harvested at mid-log phase, and washed twice before inoculation.…”

Cecal ligation and puncture induced sepsis impairs host defense against Enterococcus faecium peritonitis

“…To score liver injury, interstitial inflammation, thrombi, hepatocellular necrosis and portal inflammation were analyzed. Lungs were scored for interstitial inflammation, edema, pleuritis and thrombi [22].…”