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Role of Estrogen Receptors in Lung Function

雌激素受体在肺功能中的作用

基本信息

批准号：
8336630
负责人：
Darryl C Zeldin
金额：
$ 5.73万
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8336630
关键词：
Acute Allergens Androgens Asthma Bleomycin Breathing Bronchoalveolar Lavage Fluid Cells Characteristics Chronic Obstructive Airway Disease Collagen Complex Data Data Analyses Deposition Endotoxins Estrogen Receptor alpha Estrogen Receptors Estrogens Exhibits Experimental Models Exposure to Female Fibrosis Gender Gender Role Gene Targeting Goals Gonadal Steroid Hormones High Prevalence Histopathology Hormone replacement therapy Hour Human Immune Infiltration Inflammation Inflammatory Inflammatory Response Knockout Mice Lipopolysaccharides Lung Lung Compliance Lung diseases Measures Mediating Menstruation Methods Modeling Mus Muscarinics Oral Contraceptives Organ Outcome Pathogenesis Phenotype Physiological Play Pregnancy Prevalence Proteins Puberty Pulmonary Fibrosis Reporting Resistance Respiration Respiratory Mechanics Respiratory System Respiratory physiology Role Sex Characteristics Stimulus Surveys Symptoms System Testosterone Woman Work aerosolized airway hyperresponsiveness airway inflammation design environmental agent environmental chemical human ESR1 protein improved indexing indium-bleomycin male men methacholine natural hypothermia neutrophil new therapeutic target non-genomic novel pulmonary function receptor receptor expression receptor function response sex toll-like receptor 4

项目摘要

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.

最近几项研究的证据表明，性别和性激素在改变肺功能和包括哮喘和肺纤维化在内的肺部疾病的发病机制中起作用。事实上，我们对两项大型全国性调查数据的分析表明，在青春期后和绝经前，女性患哮喘的比例高于男性。据报道，在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得到证实。口服避孕药和激素替代疗法与改善肺功能和减少哮喘加重有关。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以及与具有雌激素和雄激素作用的环境化学物质的接触增加相一致。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，但这些关联背后的机制仍未得到研究。雌激素通过α或β er介导转录和非基因组效应。这两种受体都在肺中表达，但它们在肺中的功能在很大程度上是未知的。使用基因靶向策略培养缺乏α - er （aERKO）或β - er （bERKO）的小鼠。先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种er中的一种或两种。重要的是，没有研究检查这些小鼠在基础条件下或环境相关刺激后的肺表型。因此，这两种er在肺中的功能作用仍未被发现。我们发现雌激素受体α敲除小鼠表现出多种肺功能异常，并且在基础条件下气道对吸入甲基胆碱的反应性增强。这与肺中M2毒蕈碱受体表达和功能降低有关。缺乏雌激素受体α也会导致气道反应性增加，而不会增加过敏原致敏和挑战后的炎症。这些数据表明雌激素受体- α是呼吸的重要调节因子，为解释性激素调节气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。我们还研究了性别对幼年小鼠肺功能和呼吸力学的影响，以及对气管内脂多糖（LPS，内毒素）诱导的急性气道炎症和高反应性的影响。基础肺功能特征在幼稚的男性和女性之间没有差异，但男性在雾化甲胆碱刺激后表现出明显高于女性的气道反应性，这可以通过呼吸系统阻力和弹性的增加来证明。LPS给药后，男性比女性出现更严重的低体温和更大的气道高反应性。炎症指标，包括支气管肺泡灌洗液总细胞、中性粒细胞和TNFalpha含量，在LPS给药后6小时，男性高于女性，而全肺toll样受体-4 （TLR-4）蛋白水平在治疗组之间没有差异，这表明TLR-4在LPS暴露前后的差异表达并不是观察到的炎症结果的基础。性腺切除术减少了男性的气道炎症，但没有改变女性的炎症，而对完整女性施用外源性睾酮使其炎症反应增加到完整男性的水平。lps诱导的气道高反应性在阉割的雄性中也有所降低，而在给予外源性睾酮的雌性中则有所增加。总的来说，这些数据表明，幼年小鼠的气道反应性受到性别的影响，与雌性相比，雄性小鼠对LPS的气道炎症和功能反应更大。这些性别差异至少部分是由雄激素的作用介导的。最近，我们利用博莱霉素诱导的小鼠肺纤维化模型来检查生理和病理结果的潜在性别差异。测量的终点包括侵袭性肺功能评估、免疫反应、肺胶原沉积和肺纤维化的定量组织学分析。当以总体变化或基线变化百分比表示时，雄性小鼠的基础静态肺顺应性明显高于雌性小鼠，并且在给予博来霉素后静态肺顺应性的下降更为明显。相比之下，博莱霉素治疗后肺免疫细胞浸润量和肺总胶原蛋白含量在性别间无显著差异。使用Ashcroft方法测量的总肺组织病理学评分在两性之间没有差异，而设计用于确定肺纤维化发生位置的定量组织病理学评分系统表明，在博莱霉素治疗的雄性小鼠与雌性小鼠中，紧邻气道的纤维化倾向更多。此外，阉割的雄性小鼠对博来霉素表现出类似雌性的反应，而给予外源雄激素的雌性小鼠则表现出类似雄性的反应。这些数据表明，雄激素在博来霉素给药后肺功能下降中起加剧作用，传统的纤维化测量方法可能会忽略性别间肺功能的关键差异。在设计和解释小鼠肺纤维化实验模型时，应仔细考虑性别差异。目前的工作是研究性别和性激素在控制小鼠呼吸中的作用。