Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice

Blood. 2003 Jun 15;101(12):4823-7. doi: 10.1182/blood-2002-10-3254. Epub 2003 Feb 27.

Abstract

In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/-) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/-mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/- mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/- mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis.

MeSH terms

  • Animals
  • Cytokines / blood*
  • Disseminated Intravascular Coagulation / etiology*
  • Disseminated Intravascular Coagulation / genetics
  • Endotoxins*
  • Escherichia coli
  • Fibrin / analysis
  • Fibrinogen / analysis
  • Heterozygote
  • Interleukin-1 / blood
  • Interleukin-6 / blood
  • Kidney / chemistry
  • Liver / chemistry
  • Lung / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Platelet Count
  • Protein C / genetics
  • Protein C / physiology*
  • Protein C Deficiency / genetics*
  • Tumor Necrosis Factor-alpha / analysis

Substances

  • Cytokines
  • Endotoxins
  • Interleukin-1
  • Interleukin-6
  • Protein C
  • Tumor Necrosis Factor-alpha
  • Fibrin
  • Fibrinogen