Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
Biobehavioral Laboratory, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Am J Physiol Lung Cell Mol Physiol. 2019 Nov 1;317(5):L702-L716. doi: 10.1152/ajplung.00176.2019. Epub 2019 Sep 25.
Inflammatory lung diseases affect men and women disproportionately, suggesting that fluctuations of circulating hormone levels mediate inflammatory responses. Studies have shown that ozone exposure contributes to lung injury and impairment of innate immunity with differential effects in men and women. Here, we hypothesized that 17β-estradiol enhances inflammation and airway hyperresponsiveness (AHR), triggered by ozone exposure, in the female lung. We performed gonadectomy and hormone treatment (17β-estradiol, 2 wk) in C57BL/6J female and male mice and exposed animals to 1 ppm of ozone or filtered air for 3 h. Twenty-four hours later, we tested lung function, inflammatory gene expression, and changes in bronchoalveolar lavage fluid (BALF). We found increased AHR and expression of inflammatory genes after ozone exposure. These changes were higher in females and were affected by gonadectomy and 17β-estradiol treatment in a sex-specific manner. Gonadectomized male mice displayed higher AHR and inflammatory gene expression than controls exposed to ozone; 17β-estradiol treatment did not affect this response. In females, ovariectomy reduced ozone-induced AHR, which was restored by 17β-estradiol treatment. Ozone exposure also increased BALF lipocalin-2, which was reduced in both male and female gonadectomized mice. Treatment with 17β-estradiol increased lipocalin-2 levels in females but lowered them in males. Gonadectomy also reduced ozone-induced expression of lung IL-6 and macrophage inflammatory protein-3 in females, which was restored by treatment with 17β-estradiol. Together, these results indicate that 17β-estradiol increases ozone-induced inflammation and AHR in females but not in males. Future studies examining diseases associated with air pollution exposure should consider the patient's sex and hormonal status.
炎症性肺病在男性和女性中的影响不成比例，这表明循环激素水平的波动调节炎症反应。研究表明，臭氧暴露会导致肺损伤和固有免疫功能受损，对男性和女性的影响不同。在这里，我们假设 17β-雌二醇增强了女性肺部臭氧暴露引发的炎症和气道高反应性（AHR）。我们对 C57BL/6J 雌性和雄性小鼠进行了性腺切除术和激素治疗（17β-雌二醇，2 周），并将动物暴露于 1ppm 的臭氧或过滤空气中 3 小时。24 小时后，我们测试了肺功能、炎症基因表达和支气管肺泡灌洗液（BALF）的变化。我们发现臭氧暴露后 AHR 和炎症基因表达增加。这些变化在雌性中更高，并以性别特异性的方式受到性腺切除术和 17β-雌二醇处理的影响。去势雄性小鼠暴露于臭氧后表现出更高的 AHR 和炎症基因表达，而 17β-雌二醇处理并未影响这种反应。在雌性中，卵巢切除术降低了臭氧诱导的 AHR，而 17β-雌二醇治疗恢复了这种反应。臭氧暴露还增加了 BALF 中的脂联素-2，去势的雄性和雌性小鼠中的脂联素-2 水平均降低。17β-雌二醇治疗增加了雌性的脂联素-2 水平，但降低了雄性的水平。性腺切除术还降低了臭氧诱导的雌性肺部白细胞介素-6 和巨噬细胞炎症蛋白-3 的表达，而 17β-雌二醇治疗恢复了这种表达。总之，这些结果表明，17β-雌二醇增加了女性而非男性臭氧诱导的炎症和 AHR。未来研究检查与空气污染暴露相关的疾病时，应考虑患者的性别和激素状态。
