Role of Estrogen Receptors in Lung Function

哮喘是一种慢性呼吸道疾病。尽管改进了治疗方案，但在发达国家，哮喘的患病率和严重程度似乎正在增加。这种疾病的临床特征是呼吸道阻塞和对各种刺激如乙酰胆碱(一种胆碱能激动剂，通过刺激自主神经系统的副交感神经臂而导致支气管收缩)的高反应性，组织学上表现为呼吸道炎症和浮肿、支气管平滑肌肥大和粘液腺增生。哮喘与过敏性疾病有关，大量证据表明，暴露于室内环境中的过敏原会影响哮喘的发展、持续时间和严重程度。最近的研究还表明，吸入细菌成分，如脂多糖，可导致急性和慢性气流阻塞、呼吸道炎症和气道重塑。最近几项研究的证据表明，性激素在改善肺功能和哮喘发病机制中起着重要作用。我们对两项大型全国性调查数据的分析表明，女性在青春期后和绝经前的哮喘患病率高于男性。据报道，月经前和月经期间肺功能下降和哮喘症状恶化。怀孕期间哮喘症状的改善已被证明。口服避孕药和激素替代疗法与改善肺功能和减少哮喘恶化有关。在过去30年中，哮喘患病率的上升与口服避孕药的使用增加和接触具有雌激素和雄激素作用的环境化学品的增加相吻合。虽然这些研究表明性激素、肺功能和人类哮喘之间存在复杂的关系，但这些联系背后的机制仍未得到调查。雌激素通过α或βER调节转录和非基因组效应。这两种受体都在肺中表达，但它们在这个器官中的功能在很大程度上尚不清楚。缺乏α-ER(AERKO)或β-ER(Berko)的小鼠是使用基因靶向策略培育的。以前对这些小鼠的研究已经将各种肺外器官的许多功能归因于这两个ER之一或两者。重要的是，没有研究检查这些小鼠在基础条件下或在环境相关刺激后的肺表型。因此，这两种内质网在肺中的功能作用仍未被发现。我们发现雌激素受体-α基因敲除小鼠表现出各种肺功能异常，并在基础条件下增强了对吸入乙酰甲胆碱的呼吸道反应性。这与M2受体在肺中的表达和功能减少有关。缺乏雌激素受体-α也会导致气道反应性增加，而不会增加过敏原敏化和挑战后的炎症。这些数据表明，雌激素受体-α是呼吸的重要调节因子，为解释性激素调节呼吸道反应性提供了新的机制，并为哮喘和慢性阻塞性肺疾病的治疗提供了新的靶点。

Asthma is a chronic disease of the airways. Despite improved treatment regimens, asthma prevalence and severity appear to be increasing in developed countries. This disease is characterized clinically by airway obstruction and airway hyperresponsiveness to a variety of stimuli such as methacholine (a cholinergic agonist that causes bronchoconstriction by stimulating the parasympathetic arm of the autonomic nervous system), and histologically by airway inflammation and edema, bronchial smooth muscle hypertrophy and mucus gland hyperplasia. Asthma is associated with allergic conditions and substantial evidence suggests that exposure to allergens in the indoor environment affects the development, persistence and severity of asthma. Recent studies also demonstrate that inhalation of bacterial components such as LPS can cause acute and chronic airflow obstruction, airway inflammation, and airway remodeling. Evidence from several recent studies suggests a role for sex hormones in modifying lung function and in the pathogenesis of asthma. 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