Steady-state estradiol triggers a unique innate immune response to allergen resulting in increased airway resistance.
Steady-state estradiol triggers a unique innate immune response to allergen resulting in increased airway resistance.
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DOI：
10.1186/s13293-022-00483-7
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发表时间：
2023-01-06
影响因子：
7.9
通讯作者：
Paine III, Robert
中科院分区：
文献类型：
--
作者：
Warren, Kristi J. J.;Deering-Rice, Cassandra;Huecksteadt, Tom;Trivedi, Shubhanshi;Venosa, Alessandro;Reilly, Christopher;Sanders, Karl;Clayton, Frederic;Wyatt, Todd A. A.;Poole, Jill A. A.;Heller, Nicola M. M.;Leung, Daniel;Paine III, Robert
哮喘是一种慢性呼吸道疾病，在生殖年中女性比男性更容易发生。人口研究集体表明，长期使用口服避孕药减少了育龄妇女哮喘的发病。在目前的研究中，我们假设稳定的雌激素水平将减少气道炎症和对乙酰甲胆碱攻击的高反应性。将去卵巢的BALB/c小鼠皮下注射雌激素(雌激素，OVX-E2)和安慰剂(OVX-安慰剂)，皮下注射雌激素[68 ± 2 pg/mL]，然后进行卵白蛋白致敏和激发。结合乙酰甲胆碱激发，进行免疫表型分析，将炎症蛋白和免疫群体与侵入性肺力学技术测量的较好或较差的肺结果相关联。组织学分析显示，与其他组相比，使用稳态雌激素颗粒(OVX-E2-OVA)的卵巢切除(OVX)动物的呼吸道周围细胞总数和粘液染色增加，导致炎症评分增加，与其他组相比，包括雌性假手术组(F-Untired-OVA)和植入安慰剂颗粒的OVX(OVX-Pl-OVA)。雾化吸入乙酰胆碱后，OVX-E2-OVA组的气道阻力(RR)和肺弹性(ERS)较F-完整OVA组增加。免疫表型分析显示，在所有实验中，稳态雌激素减少了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或呼吸道中减少，但我们在剩余的肺组织中发现中性粒细胞、CD3+T细胞或CD19+B细胞没有变化。同样，在BAL中，OVX-E2-OVA处理组的炎性细胞因子(IL-5和IL-13)也低于雌性完整OVA小鼠，但在肺组织中，IL-5、IL-13和IL-33在OVX-E2-OVA和F完整OVA小鼠中相似。从肺中分离ILC2，用外源性IL-33刺激。当这些ILC2从OVX-E2-OVA动物中分离出来时，它们的细胞因子和趋化因子的表达减少，表明稳态雌激素抑制了IL-33介导的ILC2的激活。针对雌激素受体的治疗可能对嗜酸性粒细胞、ILC2和潜在的其他免疫群体具有限制作用，这些免疫群体可能会改善那些经历围绝经期哮喘恶化的女性的哮喘症状，但需要注意的是，随着时间的推移，长期使用雌激素或激素受体调节剂可能会对肺微环境有害。稳定的雌激素水平与过敏性炎症的变化有关。当E2维持在与排卵卵泡中期相当的水平时，粘液的产生和呼吸道的高反应性就会增加。雌激素减少变应原挑战后的嗜酸性粒细胞和ILC2。雌激素对肺组织中性粒细胞和CD19+B细胞无明显影响。
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. Steady levels of estrogen are associated with changes in allergic inflammation. When E2 is maintained at a level comparable to the mid-follicular phase of ovulation mucus production and airway hyperreactivity are increased. Estrogen reduces eosinophils and ILC2 following allergen challenges. Neutrophils and CD19+ B cells were unaffected in the lung tissues by estrogen treatment.
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DOI：
10.1152/ajplung.00206.2019
发表时间：
2020-01-01
影响因子：
4.9
作者：
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Sathish, Venkatachalem
影响因子：
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影响因子：
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作者：
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Takei, Fumio
影响因子：
30.5
作者：
Bernink, Jochem H.;Ohne, Yoichiro;Humbles, Alison A.
通讯作者：
Humbles, Alison A.
DOI：
10.1016/0002-9378(77)90733-5
发表时间：
1977-01-01
影响因子：
9.8
作者：
BRENNER, PF;MISHELL, DR;GOEBELSMANN, U
通讯作者：
GOEBELSMANN, U