Estrogen Receptor β Agonism Increases Survival in Experimentally Induced Sepsis and Ameliorates the Genomic Sepsis Signature: A Pharmacogenomic Study

Background. Nonsteroidal agonists have been developed that selectively bind to and activate estrogen receptor β (ERβ) rather than estrogen receptor α (ERα). ERβ is expressed equally in both male and female mammals in multiple extragonadal tissues. Work reported elsewhere has demonstrated that ERβ agonists have beneficial effects in multiple (but not all) models of inflammatory diseases and also increase survival in experimentally induced sepsis. Methods. In these experiments, ERβ agonists (ERB-041 or WAY-202196) were compared with vehicle control in the murine cecal ligation and puncture (CLP) model and in the pneumococcal pneumonia model of sepsis. The effect of WAY-202196 on the gene expression profile in the CLP model was further studied by transcriptome analysis of lung and small intestine tissue samples. Results. ERβ agonists provided a significant survival benefit in both experimental models of bacterial sepsis. This survival advantage was accompanied by reduced histologic evidence of tissue damage, reduced transcription of multiple proinflammatory proteins by transcriptome analysis and was not associated with increased bacterial outgrowth. Conclusions. ERβ agonist administration provided a survival advantage in septic animals and appears to be a promising therapeutic modality in sepsis.