Chronic intermittent hypoxia modulates corneal fibrotic markers and inflammatory cytokine expression in a sex-dependent manner

Abstract

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.