Role of Estrogen Receptors in Lung Function

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Evidence from several recent studies suggests a role for sex and sex hormones in modifying lung function and in the pathogenesis of lung diseases including asthma and lung fibrosis. Indeed, our analysis of data from two large national surveys indicates a higher prevalence of asthma among women compared to men after puberty and before menapause. Reduction in pulmonary function and worsening of asthma symptoms before and during menses has been reported. Improvements in asthma symptoms during pregnancy have been demonstrated. Oral contraceptives and hormone replacement therapy are associated with improved pulmonary function and decreased asthma exacerbation. The rise in asthma prevalence rates in the last 30 years coincides with the increased use of oral contraceptives and increased exposure to environmental chemicals with estrogenic and androgenic actions. While these studies suggest a complex relationship between sex hormones, lung function and asthma in humans, the mechanisms underlying these associations remain uninvestigated. Estrogens mediate both transcriptional and non-genomic effects via alpha or beta ERs. Both receptors are expressed in the lung but their functions in this organ are largely unknown. Mice lacking either the alpha-ER (aERKO) or the beta-ER (bERKO) were developed using gene targeting strategies. Previous studies with these mice have ascribed numerous functions in various extrapulmonary organs to either or both of the two ERs. Importantly, no studies have examined the lung phenotype of these mice under basal conditions or after environmentally relevant stimuli. Consequently the functional roles of the two ERs in the lung remains undiscovered. We found that estrogen receptor-alpha knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-alpha also leads to increased airway responsiveness without increased inflammation following allergen sensitization and challenge. These data suggest that the estrogen receptor-alpha is a critical regulator of respiration, provide a novel mechanism to explain sex hormone modulation of airway responsiveness, and identify a new therapeutic target for asthma and chronic obstructive pulmonary disease. We also examined the influence of gender on lung function and respiratory mechanics in naive mice and on acute airway inflammation and hyperresponsiveness induced by intratracheal lipopolysaccharide (LPS, endotoxin) administration. Basal lung function characteristics did not differ between naove males and females, but males demonstrated significantly greater airway responsiveness than females following aerosolized methacholine challenge as evidenced by increased respiratory system resistance and elastance. Following LPS administration, males developed more severe hypothermia and greater airway hyperresponsiveness than females. Inflammatory indices including bronchoalveolar lavage fluid total cells, neutrophils and TNFalpha content were greater in males than in females 6 hours following LPS administration, whereas whole lung Toll-like receptor-4 (TLR-4) protein levels did not differ among treatment groups, suggesting that differential expression of TLR-4 before or after LPS exposure did not underlie the observed inflammatory outcomes. Gonadectomy decreased airway inflammation in males but did not alter inflammation in females, while administration of exogenous testosterone to intact females increased their inflammatory responses to levels observed in intact males. LPS-induced airway hyperresponsiveness was also decreased in castrated males and was increased in females administered exogenous testosterone. Collectively, these data indicate that airway responsiveness in naive mice is influenced by gender,and that male mice have exaggerated airway inflammatory and functional responses to LPS compared to females. These gender differences are mediated, at least in part, by effects of androgens. More recently, we utilized a bleomycin-induced pulmonary fibrosis model in mice to examine potential sex differences in physiological and pathological outcomes. Endpoints measured included invasive lung function assessment, immunological response, lung collagen deposition, and a quantitative histological analysis of pulmonary fibrosis. Male mice had significantly higher basal static lung compliance than female mice and a more pronounced decline in static compliance following bleomycin administration when expressed as overall change or percentage of baseline change. In contrast, there were no significant differences between the sexes in immune cell infiltration into the lung or in total lung collagen content post-bleomycin. Total lung histopathology scores measured using the Ashcroft method did not differ between the sexes while a quantitative histopathology scoring system designed to determine where within the lung the fibrosis occurred indicated a tendency towards more fibrosis immediately adjacent to airways in bleomycin-treated male vs. female mice. Furthermore, castrated male mice exhibited a female-like response to bleomycin while female mice given exogenous androgen exhibited a male-like response. These data indicate that androgens play an exacerbating role in decreased lung function following bleomycin administration, and traditional measures of fibrosis may miss critical differences in lung function between the sexes. Gender differences should be carefully considered when designing and interpreting experimental models of pulmonary fibrosis in mice. Current work is examining role of sex and sex hormones in the control of breathing in mice.