Characterization of the role of estrogen receptors in exacerbating airway hyperresponsiveness

Clinical, animal, and epidemiological studies have suggested a higher prevalence of asthma in women than in men, implicating the sex steroids, most importantly, the estrogen in the lungs, as a key player. Estrogen is known to act through its alpha and beta receptors located on the lungs and several researchers have reported that they play a differential role in asthma. In this study, we evaluated the receptor-specific effect of estrogen in mediating Airway Hyperresponsiveness (AHR) using the estrogen receptors knock-out mice (Esr α KO and Esr β KO). Adult (8-10 weeks old) male and female C57BL/6J (WT), Esr α KO, and Esr β KO mice (n=2/8 per group) were challenged with 50 μl of House Dust Mite (HDM) solution (25 μg of HDM extract derived from two species, Dermatophagoides pteronyssinus and Dermatophagoides farinae) or vehicle (phosphate-buffered saline, PBS) intranasally for 5 weeks. At 72 hours after the last exposure, AHR was assessed through the Methacholine challenge (MCh) of varying doses (0, 3.13, 12.5, 25, 50, 100 mg/mL) using the flexiVent rodent ventilator system (SCIREQ) and immediately followed by the collection of bronchoalveolar lavage fluid (BALF) for the preparation of cytospin slides to analyze immune cells. Data analysis was done using GraphPad Prism 10.0.3, and the P-value < 0.05 was considered significant. Resistance (Rrs), Elastance (Ers), Conducting airway resistance (Rn), Tissue resistance (G), and Tissue elastance (H) were significantly increased ( P < 0.05) in male and female Esr β KO induced with HDM compared to PBS. Interestingly, Esr α KO HDM-induced mice showed a significant reduction in AHR only in the males and not the females, whereas it was not significantly different in the WT (males and females) exposed to HDM or PBS-induced. However, we observed that there was no statistically significant difference at P- value < 0.05 in the macrophage and lymphocyte count in the HDM-induced mice compared to the PBS in the estrogen receptor knockout mice and the WT. Eosinophil and neutrophil recruitments were observed in all the estrogen receptor knock-out groups exposed to HDM compared to the PBS but not in the WT, however, they were prominent in the Esr β KO but were not significant at P- value < 0.05. In conclusion, Esr β KO mice (males and females) showed declined lung function after exposure to allergens, indicating that Esr β plays an important role in AHR and understanding the mechanisms involved would help to develop novel therapeutics for the treatment of allergic airway inflammation in females. This study was supported by the National Heart Lung and Blood Institute: R01HL159764 (PS) and R03HL141618 (PS). 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.