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Gene Expression Profiling Identifies C/EBP as a Candidate Regulator of Endotoxin-induced Disseminated Intravascular Coagulation

¹ Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and ² Department of Internal Medicine, Academic Hospital and Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands

Correspondence and requests for reprints should be addressed to Sjoukje H. Slofstra, Ph.D., Center for Experimental and Molecular Medicine, G2-132, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: s.h.slofstra{at}amc.uva.nl

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/EBP (CAAT/enhancer binding protein ) was studied further. Induction of DIC in C/EBP-deficient mice decreased endotoxin-induced systemic inflammation as compared with wild-type mice, as evident from decreased plasma levels of tumor necrosis factor- and IL-6. In addition, C/EBP deficiency partly protected against DIC-induced mortality. Interestingly, C/EBP 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/EBP 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/EBP regulates specific pathologic features of this endotoxin-induced syndrome.

Key Words: microarray • endotoxemia • ischemia/reperfusion • transcription factor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Despite increased fundamental knowledge of the pathogenesis of disseminated intravascular coagulation (DIC), the exact molecular mechanisms of inflammatory DIC remain elusive. What This Study Adds to the Field We identified the transcription factor C/EBP as a regulator of endotoxin-induced DIC, as well as DIC-induced mortality and renal dysfunction.

 

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Expression Profiling and Disseminated Intravascular Coagulation: Finding Genes Gone Wild

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