George E Wahlen Salt Lake City VA Medical Center, 500 Foothill Dr., Salt Lake City, UT, USA.
The Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
Biol Sex Differ. 2023 Jan 6;14(1):2. doi: 10.1186/s13293-022-00483-7.
Asthma is a chronic airway condition that occurs more often in women than men during reproductive years. Population studies have collectively shown that long-term use of oral contraceptives decreased the onset of asthma in women of reproductive age. In the current study, we hypothesized that steady-state levels of estrogen would reduce airway inflammation and airway hyperresponsiveness to methacholine challenge.
Ovariectomized BALB/c mice (Ovx) were implanted with subcutaneous hormone pellets (estrogen, OVX-E2) that deliver consistent levels of estrogen [68 ± 2 pg/mL], or placebo pellets (OVX-Placebo), followed by ovalbumin sensitization and challenge. In conjunction with methacholine challenge, immune phenotyping was performed to correlate inflammatory proteins and immune populations with better or worse pulmonary outcomes measured by invasive pulmonary mechanics techniques.
Histologic analysis showed an increase in total cell infiltration and mucus staining around the airways leading to an increased inflammatory score in ovarectomized (OVX) animals with steady-state estrogen pellets (OVX-E2-OVA) as compared to other groups including female-sham operated (F-INTACT-OVA) and OVX implanted with a placebo pellet (OVX-Pl-OVA). Airway resistance (Rrs) and lung elastance (Ers) were increased in OVX-E2-OVA in comparison to F-INTACT-OVA following aerosolized intratracheal methacholine challenges. Immune phenotyping revealed that steady-state estrogen reduced CD3+ T cells, CD19+ B cells, ILC2 and eosinophils in the BAL across all experiments. While these commonly described allergic cells were reduced in the BAL, or airways, we found no changes in neutrophils, CD3+ T cells or CD19+ B cells in the remaining lung tissue. Similarly, inflammatory cytokines (IL-5 and IL-13) were also decreased in OVX-E2-OVA-treated animals in comparison to Female-INTACT-OVA mice in the BAL, but in the lung tissue IL-5, IL-13 and IL-33 were comparable in OVX-E2-OVA and F-INTACT OVA mice. ILC2 were sorted from the lungs and stimulated with exogenous IL-33. These ILC2 had reduced cytokine and chemokine expression when they were isolated from OVX-E2-OVA animals, indicating that steady-state estrogen suppresses IL-33-mediated activation of ILC2.
Therapeutically targeting estrogen receptors may have a limiting effect on eosinophils, ILC2 and potentially other immune populations that may improve asthma symptoms in those females that experience perimenstrual worsening of asthma, with the caveat, that long-term use of estrogens or hormone receptor modulators may be detrimental to the lung microenvironment over time.
哮喘是一种慢性气道疾病，在生育期女性中比男性更为常见。人群研究表明，长期口服避孕药可降低生育年龄女性哮喘的发病风险。在本研究中，我们假设稳定状态的雌激素水平可降低气道炎症和对乙酰甲胆碱激发的气道高反应性。
对去卵巢 BALB/c 小鼠（Ovx）进行皮下激素植入（雌激素，Ovx-E2），以提供稳定水平的雌激素[68±2pg/ml]或安慰剂植入（Ovx-Placebo），然后进行卵清蛋白致敏和激发。在与乙酰甲胆碱激发同时，进行免疫表型分析，将炎症蛋白和免疫细胞与通过侵入性肺力学技术测量的更好或更差的肺功能结果相关联。
组织学分析显示，在去卵巢（OVX）动物中，总细胞浸润和气道周围黏液染色增加，导致稳定状态雌激素植入（OVX-E2-OVA）的动物比其他组（包括女性假手术操作（F-INTACT-OVA）和 OVX 植入安慰剂（OVX-Pl-OVA））的炎症评分更高。与 F-INTACT-OVA 相比，OVA 雾化气管内乙酰甲胆碱激发后，OVX-E2-OVA 中的气道阻力（Rrs）和肺弹性阻力（Ers）增加。免疫表型分析显示，在所有实验中，稳定状态的雌激素均减少了 BAL 中的 CD3+T 细胞、CD19+B 细胞、ILC2 和嗜酸性粒细胞。虽然这些常见的过敏细胞在 BAL 或气道中减少，但在剩余的肺组织中，中性粒细胞、CD3+T 细胞或 CD19+B 细胞没有变化。同样，与 F-INTACT-OVA 小鼠相比，OVX-E2-OVA 处理的动物的 BAL 中的炎症细胞因子（IL-5 和 IL-13）也减少，但在肺组织中，IL-5、IL-13 和 IL-33 在 OVX-E2-OVA 和 F-INTACT OVA 小鼠中是可比的。从肺中分离出 ILC2，并使用外源性 IL-33 刺激它们。当它们从 OVX-E2-OVA 动物中分离出来时，这些 ILC2 的细胞因子和趋化因子表达减少，表明稳定状态的雌激素抑制了 IL-33 介导的 ILC2 激活。
靶向雌激素受体的治疗可能对嗜酸性粒细胞、ILC2 和潜在的其他免疫细胞有一定的限制作用，这可能会改善那些经历经前期哮喘恶化的女性的哮喘症状，但需要注意的是，长期使用雌激素或激素受体调节剂可能会随着时间的推移对肺部微环境造成损害。
