Gene expression profiling identifies C/EBPdelta as a candidate regulator of endotoxin-induced disseminated intravascular coagulation.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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.

• Authors: Sjoukje H Slofstra, Angelique P Groot, Maartje H P Obdeijn, Pieter H Reitsma, Hugo ten Cate, C Arnold Spek
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 176 Issue 6 Pg. 602-9 (Sep 15 2007) ISSN: 1073-449X [Print] United States
• PMID: 17600275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cebpd protein, mouse
• Endotoxins
• RNA, Messenger
• CCAAT-Enhancer-Binding Protein-delta

Topics

• Animals
• CCAAT-Enhancer-Binding Protein-delta (biosynthesis, genetics)
• Disease Models, Animal
• Disease Progression
• Disseminated Intravascular Coagulation (etiology, genetics, metabolism)
• Endotoxins (toxicity)
• Gene Expression
• In Situ Hybridization, Fluorescence
• Lung (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Polymerase Chain Reaction
• RNA, Messenger (genetics)
• Severity of Illness Index