Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice.
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.
Levi
Marcel
M
Department of Vascular Medicine/Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands. m.m.levi@amc.uva.nl
Dörffler-Melly
Janine
J
Reitsma
Pieter
P
Buller
Harry
H
Florquin
Sandrine
S
van der Poll
Tom
T
Carmeliet
Peter
P
D000818:Animals; D016207:Cytokines / Q000097:blood*; D004211:Disseminated Intravascular Coagulation / Q000209:etiology* / Q000235:genetics; D004731:Endotoxins; D004926:Escherichia coli; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D006579:Heterozygote; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008168:Lung / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010976:Platelet Count; D011486:Protein C / Q000235:genetics / Q000502:physiology*; D020151:Protein C Deficiency / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D016207:Cytokines; D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D011486:Protein C; D014409:Tumor Necrosis Factor-alpha; D005337:Fibrin; D005340:Fibrinogen