Estrogen receptor (ER) β agonists have been demonstrated to possess
anti-inflammatory properties in inflammatory disease models.
The objective of this study was to determine
whether ERβ agonists affect in vitro and in vivo preclinical models of
asthma.
mRNA expression assays were validated in human and
rodent tissue panels. These assays were then used to measure expression
in human cells and our characterized rat model of
allergic asthma. ERB-041
[7-ethenyl-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol],
an ERβ agonist, was profiled on cytokine release
from interleukin-1β-stimulated human airway smooth muscle (HASM) cells
and
in the rodent asthma model. Although ERβ expression
was demonstrated at the gene and protein level in HASM cells, the
agonist
failed to have an impact on the inflammatory
response. Similarly, in vivo, we observed temporal modulation of ERβ
expression
after antigen challenge. However, the agonist
failed to have an impact on the model endpoints such as airway
inflammation,
even though plasma levels reflected linear compound
exposure and was associated with an increase in receptor activation
after
drug administration. In these modeling systems of
airway inflammation, an ERβ agonist was ineffective. Although ERβ
agonists
are anti-inflammatory in certain models, this novel
study would suggest that they would not be clinically useful in the
treatment
of asthma.