Dimitropoulou Christiana, Drakopanagiotakis Fotios, Chatterjee Anuran, Snead Connie, Catravas John D
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, 30912-2300, USA.
Lung. 2009 Mar-Apr;187(2):116-27. doi: 10.1007/s00408-008-9129-z. Epub 2008 Dec 13.
We previously reported that 17beta-estradiol (E2) prevents hyperresponsiveness to carbachol of murine asthmatic tracheal rings in vitro. We now investigated whether E2 is similarly effective in reducing airway hyperreactivity in a murine model of allergic asthma in vivo. Female ovariectomized BALB/c mice were rendered asthmatic by a 25-day protocol of sensitization to ovalbumin. Under positive-pressure ventilation, anesthetized asthmatic mice exhibited a dramatic increase in airway responsiveness to increasing doses of inhaled methacholine compared to PBS-sensitized controls, as reflected in decreased dynamic compliance of the respiratory system and increased tissue damping, tissue elastance, and airway resistance. Furthermore, asthmatic mice exhibited hypercellularity and increased protein concentration in the bronchoalveolar lavage, strong signs of peribronchial cuffing with inflammatory cells and increased goblet cell activity. To test the effects of estrogen, three additional groups of mice were implanted subcutaneously with different amounts of slow-release E2 pellets at the time of ovariectomy and rendered asthmatic as before. E2 dose-dependently inhibited airway hyperresponsiveness to methacholine, reduced bronchoalveolar lavage hypercellularity, and virtually eliminated histologic signs of inflammation and goblet cell hyperactivity. The inflammation and airway hyperactivity in asthmatic mice was associated with an increase in bronchoalveolar lavage levels of TGFbeta1, which was completely abolished in E2-treated asthmatic mice. We conclude that estrogen replacement therapy effectively ameliorates the pathologic profile of murine allergic asthma.
我们之前报道过，17β-雌二醇（E2）在体外可预防小鼠哮喘气管环对卡巴胆碱的高反应性。我们现在研究E2在体内过敏性哮喘小鼠模型中减轻气道高反应性方面是否同样有效。通过对卵清蛋白进行25天的致敏方案，使雌性去卵巢BALB/c小鼠诱发哮喘。在正压通气下，与用磷酸盐缓冲盐水（PBS）致敏的对照小鼠相比，麻醉的哮喘小鼠对递增剂量吸入的乙酰甲胆碱的气道反应性显著增加，这反映在呼吸系统动态顺应性降低以及组织阻尼、组织弹性和气道阻力增加。此外，哮喘小鼠支气管肺泡灌洗显示细胞增多且蛋白浓度增加，有明显的支气管周围炎性细胞套袖样改变迹象以及杯状细胞活性增加。为了测试雌激素的作用，另外三组小鼠在去卵巢时皮下植入不同量的缓释E2丸剂，并像之前一样诱发哮喘。E2剂量依赖性地抑制对乙酰甲胆碱的气道高反应性，降低支气管肺泡灌洗中的细胞增多，并几乎消除炎症的组织学迹象和杯状细胞的高活性。哮喘小鼠的炎症和气道高活性与支气管肺泡灌洗中转化生长因子β1（TGFβ1）水平升高有关，而在E2治疗的哮喘小鼠中这种升高完全被消除。我们得出结论，雌激素替代疗法可有效改善小鼠过敏性哮喘的病理特征。
