Estrogen Metabolites Modulate Airway Hyperreactivity in a Murine Model of Asthma

Abstract

Objective: Airway hyperreactivity (AHR) and remodeling are the key contributors to airway changes in asthma resulting in airway narrowing and resistance to airflow. Sex-steroid signaling, especially estrogen’s differential role in asthma undoubtedly questions its prime involvement in regulating airway structure and function in context to asthma. Evidence from cardiovascular (CV) and reproductive systems suggests that estrogen metabolites particularly 2-hydroxyestradiol (2HE) and 16α-hydroxyestradiol (16αHE2) influence a multitude of cellular functions. Accordingly, the aim of this study is to determine how estrogen metabolites regulate AHR and remodeling using a mouse model of asthma. Methods: WT C57BL/6J (male and female) mice were procured from Jackson Laboratory. Experimental animals were administered with PBS, 2-HE (2 mg/kg), 16αHE2 (2 mg/kg) with/without MA intranasally on alternate days for 28 days. On day 29, mice were anesthetized and subjected to SCIREQ flexiVent to measure Lung mechanics like airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and lung tissue samples processed for histology using hematoxylin and eosin (H&E) staining and Sirius-red and fast-green (SRFG). Results: MA-challenged group increased airway Rrs and reduced Crs in response to methacholine (MCh) in both male and female mice with profound effects in female mice. Animals exposed to MA and administered with 16αHE2 showed significant increase the Rrs while 2-HE downregulated the MA effect. The exacerbated effect of 16αHE2 on Rrs was significantly higher in MA-challenged female mice compared to male mice. Histology study including H&E and SRFG stained lung sections show increased ASM mass in 16αHE2 exposed mixed MA challenged mice. Whereas 2HE reversed MA induced effect. DLC in BAL showed increased neutrophils and eosinophils in MA challenged mice, this was attenuated by 2HE. Conclusion: This study highlights the distinct role of estrogen metabolites in regulating airway hyperresponsiveness and remodeling in the context of asthma. Thus, providing possible therapeutic potential for observed sex differences in asthma. Acknowledgment: Supported by NIH grant R01-HL146705 (Sathish). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.