Author(s): Slofstra SH, Groot AP, Obdeijn MH, Reitsma PH, ten Cate H,
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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.
This article was published in Am J Respir Crit Care Med
and referenced in Emergency Medicine: Open Access