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气道阻塞， 气流受损尽管在诊断和治疗方面取得了重大进展，但哮喘仍然是一个严重的疾病。 严重的健康问题影响了美国2500多万患者， 世界据报道，哮喘的性别和性别差异具有很好的特征，发病率也有变化 在生活中。从青春期开始，到中年达到高峰，女性哮喘患病率增加 哮喘恶化的比率也高于男性。造成这些差异的原因尚不清楚;然而， 研究表明，由激素控制的性别特异性炎症机制有助于差异 气道对环境刺激的反应性。尽管如此，哮喘的实验模型并没有 探索了性激素对女性和男性肺部炎症机制的作用， 研究已经探索了在变性妇女的肺中使用雌激素的女性化激素治疗的效果。之前 我们实验室使用小鼠模型的研究报告了性别差异和发情的影响， 循环和循环性激素在炎症反应的环境暴露。基于这些 研究发现，我们假设女性性激素，特别是雌激素，有助于哮喘表型 通过激活雌激素受体介导的炎症机制在肺中发生。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 哮喘的影响。在目标1中，我们将确定性染色体补体的贡献（XX与XY） vs.性激素在哮喘表型中的作用，通过建立小鼠屋尘螨哮喘模型， 四核心基因型（FCG）模型。在目标2中，我们将研究雌激素对HDM诱导的 使用雌二醇治疗的雄性和雌性性腺切除小鼠的哮喘结果，以及支气管 来自男性和女性健康和哮喘患者的上皮细胞在存在/不存在HDM的情况下暴露于HDM 雌激素受体激动剂/拮抗剂。在目标3中，我们将确定核（ER）和膜的作用- 结合（GPER-1）雌激素受体在HDM诱导的雌激素介导的炎症机制中的作用 哮喘，使用ER和GPER 1敲除小鼠。我们的研究将是第一个描述雌激素介导的 男性和女性肺中哮喘表型的炎症机制，有助于 说明个体间差异的性别和性别特异性因素的特征，以及 女性化激素治疗在肺病理学中的作用。我们希望我们的研究能有助于发展 潜在的性别和性别特异性治疗以及治疗药物剂量的建议 预防顺性和变性女性的哮喘。

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.