Estrogen receptor beta 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 beta (ERbeta) rather than estrogen receptor alpha (ERalpha). ERbeta is expressed equally in both male and female mammals in multiple extragonadal tissues. Work reported elsewhere has demonstrated that ERbeta 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, ERbeta 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
ERbeta 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
ERbeta agonist administration provided a survival advantage in septic animals and appears to be a promising therapeutic modality in sepsis.
Christaki
Eirini
E
Infectious Disease Division, Memorial Hospital of Rhode Island, Warren Alpert School of Medicine of Brown University, Providence, Rhode Island, USA.
Opal
Steven M
SM
Keith
James C
JC
Kessinian
Nubar
N
Palardy
John E
JE
Parejo
Nicolas A
NA
Lavallie
Edward
E
Racie
Lisa
L
Mounts
William
W
Malamas
Michael S
MS
Mewshaw
Richard E
RE
Harris
Heather A
HA
Vlasuk
George P
GP
D000818:Animals; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000096:biosynthesis / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009284:Naphthols / Q000627:therapeutic use*; D010080:Oxazoles / Q000627:therapeutic use*; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D014158:Transcription, Genetic / Q000187:drug effects
C478102:ERB 041; D047629:Estrogen Receptor beta; D009284:Naphthols; D010080:Oxazoles; C501752:3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile