A protein C deficiency exacerbates inflammatory and hypotensive responses in mice during polymicrobial sepsis in a cecal ligation and puncture model.
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.
W.M. Keck Center for Transgene Research, Department of Chemistry and Biochemistry, 434 Stepan Hall of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Jorge G
JG
Ganopolsky
Francis J
FJ
Castellino
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D001779:Blood Coagulation Factors / Q000032:analysis; D002432:Cecum / Q000473:pathology*; D016207:Cytokines / Q000032:analysis; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005838:Genotype; D007022:Hypotension / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008026:Ligation; D008297:Male; D051379:Mice; D010538:Peritonitis / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D020151:Protein C Deficiency / Q000235:genetics / Q000378:metabolism*; D011677:Punctures; D012333:RNA, Messenger / Q000032:analysis; D018805:Sepsis / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*
D001779:Blood Coagulation Factors; D016207:Cytokines; D017931:DNA Primers; D012333:RNA, Messenger