Gene expression profiling identifies C/EBPdelta as a candidate regulator of endotoxin-induced disseminated intravascular coagulation.
BACKGROUND
A runaway inflammatory response to systemic infection or severe trauma is characterized by the activation of a diversity of pathways, ultimately resulting in the development of disseminated intravascular coagulation (DIC) and multiorgan failure.


OBJECTIVE
Despite increased fundamental knowledge of the pathogenesis of DIC, the exact molecular mechanisms remain elusive. We aimed therefore to improve our understanding of the molecular pathways underlying endotoxin-induced DIC.


METHODS
We performed large-scale gene expression profiling in the liver of mice during the onset of endotoxin-induced DIC. The relevance of an identified candidate gene involved in endotoxin-induced DIC was subsequently assessed in the generalized Shwartzman reaction.


RESULTS
Approximately 5% of over 20,000 genes were differentially regulated. In addition to well-established sepsis-associated genes, such as macrophage inflammatory protein 1, plasminogen activator inhibitor 1, CD14, and A20, we identified several novel candidates for inflammatory disease of which the transcription factor C/EBPdelta (CAAT/enhancer binding protein delta) was studied further. Induction of DIC in C/EBPdelta-deficient mice decreased endotoxin-induced systemic inflammation as compared with wild-type mice, as evident from decreased plasma levels of tumor necrosis factor-alpha and IL-6. In addition, C/EBPdelta deficiency partly protected against DIC-induced mortality. Interestingly, C/EBPdelta deficiency seemed mainly protective by improving renal function. This latter notion was confirmed in an experimental model of renal ischemia/reperfusion injury in which C/EBPdelta deficiency reduced ischemia/reperfusion-induced creatinine and urea levels.


CONCLUSIONS
Our results endorse the usefulness of gene expression profiling in identifying novel mediators of DIC by showing that C/EBPdelta regulates specific pathologic features of this endotoxin-induced syndrome.
Slofstra
Sjoukje H
SH
Center for Experimental and Molecular Medicine, G2-132, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. s.h.slofstra@amc.uva.nl
Groot
Angelique P
AP
Obdeijn
Maartje H P
MH
Reitsma
Pieter H
PH
ten Cate
Hugo
H
Spek
C Arnold
CA
D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004211:Disseminated Intravascular Coagulation / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity; D015870:Gene Expression; D017404:In Situ Hybridization, Fluorescence; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*; D012720:Severity of Illness Index
C497253:Cebpd protein, mouse; D004731:Endotoxins; D012333:RNA, Messenger; D051743:CCAAT-Enhancer-Binding Protein-delta