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.
Ganopolsky
Jorge G
JG
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.
Castellino
Francis J
FJ
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