Bradshaw Jessica L, Vasini Brenda, Mabry Steve, Hefley Brenna S, Wilson E Nicole, Gardner Jennifer J, Cunningham Rebecca L, Karamichos Dimitrios
Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, Texas, USA; North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Exp Eye Res. 2025 Jun;255:110358. doi: 10.1016/j.exer.2025.110358. Epub 2025 Mar 24.
Chronic intermittent hypoxia (CIH) is a commonly observed condition in patients suffering from obstructive sleep apnea (OSA). Previous studies link CIH to fibrosis, inflammation, and hormonal dysregulation across various tissues. Yet, the effect of CIH in the cornea is unknown. Moreover, women and men diagnosed with OSA present with diverse symptoms, suggesting sex-specific pathophysiology at play. Thus, we used a rat model to assess the impact of CIH and sex on protein expression of corneal fibrotic markers (α-SMA, COL III, cFN, TSP-1), proinflammatory cytokines (IL-1 α, IL-17, IL-18, and IFN-γ), and hormone receptors (ERα, ERβ, GPER, GnRH-R, and LH-R). Male and female Sprague Dawley rats were exposed to normoxic or CIH conditions during their sleep cycle for 14 days. Extracted corneal proteins were subjected to Western blot and multiplex magnetic bead analysis. Our results reveal sex differences in fibrotic and inflammatory markers in the cornea, whereby female corneas exhibit higher levels of fibrotic markers, while male corneas exhibit increased inflammatory cytokines. CIH exposure resulted in elevated levels of α-SMA and pro-inflammatory cytokines in female corneas, while there was no impact on fibrotic or inflammatory markers in male corneas. Additionally, CIH exposure reduced hormone receptors in male and female corneas in a sex-dependent manner. Correlation analyses identified associations of corneal hormone receptors with corneal fibrotic and pro-inflammatory markers that were dependent on sex, with female corneas demonstrating stronger correlations compared to male corneas. Altogether, our data suggests hormone-mediated signaling may contribute to CIH-mediated corneal fibrosis and inflammatory phenotypes, especially in females.
慢性间歇性缺氧（CIH）是阻塞性睡眠呼吸暂停（OSA）患者中常见的一种情况。先前的研究将CIH与各种组织中的纤维化、炎症和激素失调联系起来。然而，CIH对角膜的影响尚不清楚。此外，被诊断为OSA的女性和男性表现出不同的症状，这表明存在性别特异性的病理生理机制。因此，我们使用大鼠模型来评估CIH和性别对角膜纤维化标志物（α-SMA、III型胶原蛋白、细胞外基质蛋白聚糖、血小板反应蛋白-1）、促炎细胞因子（IL-1α、IL-17、IL-18和IFN-γ）以及激素受体（雌激素受体α、雌激素受体β、G蛋白偶联雌激素受体、促性腺激素释放激素受体和促黄体生成素受体）蛋白表达的影响。雄性和雌性Sprague Dawley大鼠在睡眠周期中暴露于常氧或CIH环境中14天。提取的角膜蛋白进行蛋白质印迹和多重磁珠分析。我们的结果揭示了角膜中纤维化和炎症标志物的性别差异，其中雌性角膜表现出较高水平的纤维化标志物，而雄性角膜表现出促炎细胞因子增加。CIH暴露导致雌性角膜中α-SMA和促炎细胞因子水平升高，而对雄性角膜中的纤维化或炎症标志物没有影响。此外，CIH暴露以性别依赖的方式降低了雄性和雌性角膜中的激素受体。相关性分析确定了角膜激素受体与角膜纤维化和促炎标志物之间的关联，这种关联取决于性别，与雄性角膜相比，雌性角膜表现出更强的相关性。总之，我们的数据表明激素介导的信号传导可能导致CIH介导的角膜纤维化和炎症表型，尤其是在女性中。
