A protein C deficiency exacerbates inflammatory and hypotensive responses in mice during polymicrobial sepsis in a cecal ligation and puncture model.

Abstract

During the systemic inflammatory state induced by sepsis, the potential for coagulopathy exists because of up-regulation of natural procoagulants and anti-fibrinolytics, and down-regulation of natural anti-coagulants, with protein C (PC) being a critical example of the latter case. PC functions as an anti-coagulant, profibrinolytic, and anti-inflammatory agent, and, thus, its administration or deficiency may affect the course and outcome of sepsis in patients. In this study, a cecal ligation and puncture model of septic peritonitis was applied to wild-type mice and littermates with a targeted heterozygous deficiency of PC (PC(+/-)) to characterize the importance of a PC-deficiency on polymicrobial sepsis. An enhanced mortality rate was found to accompany a PC deficiency. Plasma cytokines, as well as organ-specific expression of cytokine transcripts, were elevated in PC(+/-) mice. No signs of severe disseminated intravascular coagulation (DIC) were observed in wild-type or PC(+/-) mice, as indicated by an increase in fibrinogen levels and the invariability of platelet counts after cecal ligation and puncture. Consumption of coagulation factors was similar in both genotypes and a decrease in the PC mRNA and protein levels was more prominent in PC(+/-) mice. Renal and organ muscle damage was enhanced in PC(+/-) mice, as shown by increases in plasma blood urea nitrogen, creatinine, and creatinine kinase. Hypotension and bradycardia were more enhanced in PC(+/-) mice than in wild-type mice, thus provoking a more severe septic shock response. Thus, the hemodynamic role of PC during sepsis is of critical importance to the outcome of the disease.

• Authors: Jorge G Ganopolsky, Francis J Castellino
• Journal: The American journal of pathology (Am J Pathol) Vol. 165 Issue 4 Pg. 1433-46 (Oct 2004) ISSN: 0002-9440 [Print] United States
• PMID: 15466407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Blood Coagulation Factors
• Cytokines
• DNA Primers
• RNA, Messenger

Topics

• Animals
• Blood Coagulation (physiology)
• Blood Coagulation Factors (analysis)
• Cecum (pathology)
• Cytokines (analysis)
• DNA Primers
• Disease Models, Animal
• Female
• Gene Expression
• Genotype
• Hypotension (epidemiology, etiology, physiopathology)
• Immunohistochemistry
• Inflammation (metabolism, pathology)
• Ligation
• Male
• Mice
• Peritonitis (microbiology, pathology, physiopathology)
• Polymerase Chain Reaction
• Protein C Deficiency (genetics, metabolism)
• Punctures
• RNA, Messenger (analysis)
• Sepsis (microbiology, pathology, physiopathology)