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Role of Differential Estrogen Receptor Activation on Airway Hyperreactivity and Remodeling in a Murine Model of Asthma.

Evidence suggest that airway hyperresponsiveness (AHR) is a characteristic feature of asthma. Epidemiological studies confirm severity of asthma is greater in women, suggesting a critical role of female sex steroid hormones (especially estrogen). Also, very few in vivo studies report role of sex steroid hormones in asthma; however, sequence of events through differential activation of estrogen receptors (ERs) remain unanswered in asthmatic airways. Toward this goal, our recent in vitro findings indicate increased expression of ERβ in asthmatic airway smooth muscle (ASM) and that its activation by ERβ specific agonist downregulated airway remodeling. In this study, we translated the in vitro findings in murine asthma model and examined the differential role of ER activation in modulating lung mechanics. C57BL/6J male, female and ovariectomized (OVX) mice were exposed to mixed allergen (MA) and subcutaneously implanted with sustained release pellets of placebo, ERα-agonist (PPT) and/or ERβ-agonist (WAY) and evaluated for respective effects on airway mechanics, biochemical, molecular and histological parameters. Mice exposed to MA showed significant increase in airway resistance, elastance, tissue-damping and decrease in compliance; pronounced effects were observed in females. Compared to PPT, WAY treatment significantly reversed MA induced changes. Increased mRNA/protein expression of ERα, ERβ and remodeling genes observed in MA treated mice were significantly reversed in WAY treated mice. This novel study indicates that activation of ERβ signaling downregulates AHR and airway remodeling and is a promising target to treat asthma.