Gonadal hormones as mediators of sex and gender influences in asthma

摘要 哮喘是一种肺部疾病，由过度的肺部炎症导致呼吸道阻塞和 气流受损。尽管哮喘的诊断和治疗取得了重大进展，但它仍然是一种 严重的健康问题影响着美国超过2500万名患者，以及全球超过3亿名患者 世界。哮喘的性别和性别差异已有报道，发病率发生了变化。 在一生中。从青春期开始并在中年达到高峰的女性哮喘患病率有所增加 而且哮喘恶化的比率比男性更高。造成这些差异的原因尚不清楚；然而， 研究表明，由荷尔蒙控制的性别特异性炎症机制导致了差异 在呼吸道对环境刺激的反应中。尽管如此，哮喘的实验模型并没有 探讨性激素在女性和男性肺部炎症机制中的作用，以及NO 研究探索了在变性妇女的肺部使用雌激素进行女性化激素治疗的效果。之前 我们实验室使用小鼠模型进行的研究报告了性别差异和发情的影响。 性激素在对环境暴露的炎症反应中的循环和循环。基于这些 结果，我们假设女性性激素，特别是雌激素，对哮喘表型有影响。 在肺部，通过雌激素受体介导的炎症机制的激活。在拟议的研究中， 我们将通过确定雌激素介导性和性别的机制来检验这一假设。 对哮喘的影响。在目标1中，我们将确定性染色体互补的贡献(XX与XY) 在哮喘表型中比较性腺激素，通过建立小鼠家尘螨(HDM)哮喘模型 四种核心基因型(FCG)模型。在目标2中，我们将研究雌激素在hdm诱导中的作用。 雌雄去性腺小鼠使用雌二醇和支气管治疗后的哮喘结果 男女健康人和哮喘患者在有无HDM暴露下的上皮细胞 雌激素受体激动剂/拮抗剂。在目标3中，我们将确定核(ER)和膜- 雌激素受体结合(GPER-1)在雌激素介导的HDM炎症机制中的作用 哮喘，采用ER和GPER1基因敲除小鼠。我们的研究将是第一个表征雌激素介导的 男性和女性肺中哮喘表型的炎症机制，有助于 说明造成个体间差异的性别因素和性别因素的特征，以及 女性化激素治疗对肺部病理生物学的影响。我们期待着我们的研究将有助于发展 潜在的针对性别和性别的治疗方法和治疗剂治疗剂量的建议 并预防顺式和变性人女性的哮喘。

ABSTRACT Asthma is a lung disease caused by exaggerated lung inflammation leading to airway obstruction and compromised airflow. Despite significant advances in its diagnosis and treatment, asthma continues to be a significant health problem affecting more than 25 million patients in the US, and over 300 million around the world. Well-characterized sex and gender differences in asthma have been reported, with changes in morbidity throughout life. Starting around puberty and peaking during mid-life, women have increased asthma prevalence and higher rates of asthma exacerbations than men. Causes of these disparities remain unclear; however, studies have shown that sex-specific inflammatory mechanisms controlled by hormones contribute to differences in airway reactivity in response to environmental stimuli. Despite this, experimental models of asthma have not explored the contributions of sex hormones to inflammatory mechanisms in the female and male lung, and no studies have explored the effects of feminizing hormone therapy with estrogen in the lungs of trans women. Prior studies from our laboratory using mouse models have reported sex differences and influences of the estrous cycle and circulating sex hormones in the inflammatory response to environmental exposures. Based on these findings, we hypothesized that female sex hormones, specifically estrogens, contribute to asthma phenotypes in the lung via activation of inflammatory mechanisms mediated by estrogen receptors. In the proposed study, we will test this hypothesis by determining the mechanisms by which estrogen mediates sex and gender influences in asthma. In Aim 1, we will determine the contributions of sex chromosome complement (XX vs. XY) vs. gonadal hormones in asthma phenotypes, by developing a mouse house dust mite (HDM) asthma model on the four core genotypes (FCG) model. In Aim 2, we will study the contributions of estrogens to HDM-induced asthma outcomes using male and female gonadectomized mice treated with estradiol, as well as bronchial epithelial cells from male and female healthy and asthma patients to exposed to HDM in the presence/absence of estrogen receptor agonists/antagonists. In Aim 3, we will determine the roles of nuclear (ER) and membrane- bound (GPER-1) estrogen receptors in estrogen-mediated mechanisms of inflammation in HDM-induced asthma, using ER and GPER1 knockout mice. Our studies will be the first to characterize estrogen-mediated mechanisms of inflammation in asthma phenotypes in the male and female lung, contributing to the characterization of sex- and gender-specific factors accounting for inter-individual differences, as well as the effects of feminizing hormone therapy in lung pathobiology. We expect that our studies would serve to develop potential sex- and gender-specific treatments and recommendations for dosage of therapeutic agents to treat and prevent asthma in cis and transgender women.