Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency.
The anticoagulant, activated protein C (aPC), possesses antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptotic properties, and the level of this protein is an important marker of acute inflammatory responses. Although infusion of aPC improves survival in a subset of patients with severe sepsis, evidence as to how aPC decreases mortality in these cases is limited. Because a total deficiency of PC shows complete neonatal lethality, no animal model currently exists to address the mechanistic relationships between very low endogenous aPC levels and inflammatory diseases. Here, we show for the first time that novel genetic dosing of PC strongly correlates with survival outcomes following endotoxin (LPS) challenge in mice. The data provide evidence that very low endogenous levels of PC predispose mice to early-onset disseminated intravascular coagulation, thrombocytopenia, hypotension, organ damage, and reduced survival after LPS challenge. Furthermore, evidence of an exacerbated inflammatory response is observed in very low PC mice but is greatly reduced in wild-type cohorts. Reconstitution of low-PC mice with recombinant human aPC improves hypotension and extends survival after LPS challenge. This study directly links host endogenous levels of PC with various coagulation, inflammation, and hemodynamic end points following a severe acute inflammatory challenge.
Lay
Angelina J
AJ
W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA.
Donahue
Deborah
D
Tsai
Meng-Ju
MJ
Castellino
Francis J
FJ
D000208:Acute Disease; D000818:Animals; D004211:Disseminated Intravascular Coagulation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000378:metabolism; D011486:Protein C / Q000378:metabolism*; D020151:Protein C Deficiency / Q000097:blood* / Q000235:genetics / Q000473:pathology*; D015996:Survival Rate
D008070:Lipopolysaccharides; D010455:Peptides; D011486:Protein C; C017422:hypotensin (snake)