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. More recently, we 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 naove 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. Current work is examining role of sex and sex hormones in the lung fibrotic and functional response to bleomycin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES101885-03
Application #
7594012
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2007
Total Cost
$366,117
Indirect Cost
City
State
Country
United States
Zip Code
Randall, Thomas A; Mullikin, James C; Mueller, Geoffrey A (2018) The Draft Genome Assembly of Dermatophagoides pteronyssinus Supports Identification of Novel Allergen Isoforms in Dermatophagoides Species. Int Arch Allergy Immunol 175:136-146
Thomas, Abe C; Nouls, John C; Driehuys, Bastiaan et al. (2011) Ventilation defects observed with hyperpolarized 3He magnetic resonance imaging in a mouse model of acute lung injury. Am J Respir Cell Mol Biol 44:648-54
Carey, Michelle A; Card, Jeffrey W; Bradbury, J Alyce et al. (2007) Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice. Am J Respir Crit Care Med 175:126-35
Carey, Michelle A; Card, Jeffrey W; Voltz, James W et al. (2007) It's all about sex: gender, lung development and lung disease. Trends Endocrinol Metab 18:308-13
Card, Jeffrey W; Voltz, James W; Ferguson, Catherine D et al. (2007) Male sex hormones promote vagally mediated reflex airway responsiveness to cholinergic stimulation. Am J Physiol Lung Cell Mol Physiol 292:L908-14
Carey, Michelle A; Card, Jeffrey W; Voltz, James W et al. (2007) The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies. Am J Physiol Lung Cell Mol Physiol 293:L272-8
Zeldin, Darryl; Card, Jeffrey W; Carey, Michelle A et al. (2007) ""Lung impedance measurements are/are not more useful than simpler measurements of lung function in animal models of pulmonary disease"". J Appl Physiol 103:1906;author reply 1909-10
Card, Jeffrey W; Carey, Michelle A; Bradbury, J Alyce et al. (2006) Gender differences in murine airway responsiveness and lipopolysaccharide-induced inflammation. J Immunol 177:621-30