The impact of hormone replacement therapy during perimenopause on lung function and inflammation in mice

<bold>Background:</bold> Mechanisms driving menopause associated asthma are unknown. We developed a mouse model of menopause associated asthma using a combination of 4-Vinylcyclohexene Diepoxide (VCD) and House Dust Mite (HDM) exposures. The goal of this study was to determine how hormone replacement therapy during perimenopause impacts lung function and inflammation. <bold>Methods:</bold> Menopausal mice (VCD) with and without exposure to HDM (to model allergic airways disease) and menopausal mice with and without hormone replacement therapy (HRT; via estrogen pellet implantation) were used. Lung function during a methacholine challenge was assessed by Flexivent. Serum, BALF and histological samples were collected for assessment and mouse tracheal epithelial cells (MTECs) were taken from each group and culture at an air-liquid interface. <bold>Results:</bold> Mice that received HRT during perimenopause had enhanced airway hyperresponsiveness (AHR) and reduced lung function compared to controls. While HRT in perimenopause resulted in decreased eosinophils in the HDM model, neutrophil levels and mucus production were unchanged. Mice receiving HRT in perimenopause had significantly increased collagen production and inflammation associated with large and small airways, independent of HDM challenge. MTECs from menopausal mice had increased transepithelial electrical resistance when grown at an air-liquid interface, which was further augmented from the cells of mice that received HRT during perimenopause. <bold>Conclusions:</bold> HRT given during perimenopause may be detrimental to lung responses, including increased AHR and decreased lung function, as well as increased tissue inflammation and airway remodeling.