Abstract |
Estrogen receptor (ER) beta agonists have been demonstrated to possess anti-inflammatory properties in inflammatory disease models. The objective of this study was to determine whether ERbeta 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 ERbeta agonist, was profiled on cytokine release from interleukin-1beta-stimulated human airway smooth muscle (HASM) cells and in the rodent asthma model. Although ERbeta 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 ERbeta 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 ERbeta agonist was ineffective. Although ERbeta agonists are anti-inflammatory in certain models, this novel study would suggest that they would not be clinically useful in the treatment of asthma.
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Authors | Matthew C Catley, Mark A Birrell, Elizabeth L Hardaker, Jorge de Alba, Stuart Farrow, Saleem Haj-Yahia, Maria G Belvisi |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 326
Issue 1
Pg. 83-8
(Jul 2008)
ISSN: 1521-0103 [Electronic] United States |
PMID | 18375789
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ERB 041
- Estrogen Receptor beta
- Inflammation Mediators
- Oxazoles
- RNA, Messenger
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Topics |
- Animals
- Asthma
(drug therapy, genetics, metabolism)
- Cells, Cultured
- Estrogen Receptor beta
(agonists, biosynthesis, genetics)
- Gene Expression Profiling
- Humans
- Inflammation
(metabolism, prevention & control)
- Inflammation Mediators
(metabolism, physiology)
- Male
- Oxazoles
(pharmacology, therapeutic use)
- RNA, Messenger
(biosynthesis, genetics)
- Rats
- Rats, Inbred BN
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