Association of Obstructive Sleep Apnea Risk with Hypoxia-Inducible Factor Expression in Chronic Rhinosinusitis by...

Background/Objectives: Hypoxia and hypoxia-inducible factors (HIFs) have emerged as pivotal factors in the pathophysiology of chronic rhinosinusitis (CRS). Obstructive sleep apnea (OSA) may exacerbate hypoxia-driven sinonasal inflammation. This study evaluated the association between OSA risk and sinonasal HIF expression in CRS patients, focusing on the distinct profiles of eosinophilic (ECRS) and non-eosinophilic (NECRS) endotypes. Methods: Ethmoid mucosal tissues were collected from 64 CRS patients undergoing surgery. Patients were classified into ECRS or NECRS groups based on blood eosinophil counts, and into high- or low-risk OSA groups based on apnea-hypopnea index on polysomnography or sleep domain score from the 22-item sinonasal outcome test. Protein levels of HIF-1α, HIF-2α, and various inflammatory mediators were measured via multiplex immunoassay. Results: HIF-2α expression was significantly higher in the high-risk OSA group (116.80 ± 131.48 vs. 47.37 ± 42.14, p < 0.05), whereas HIF-1α levels were independent of OSA status. Following stratification by endotype, HIF-1α expression was significantly higher in NECRS than in ECRS (0.042 ± 0.020 vs. 0.034 ± 0.024, p < 0.05). Notably, high-risk OSA was associated with markedly increased HIF-2α only within the NECRS subgroup (115.52 ± 61.07 vs. 47.97 ± 31.03, p < 0.05). Correlation analyses demonstrated endotype-specific inflammatory coupling, showing that HIF-1α and HIF-2α were selectively linked to MMP-9 (r = 0.689, p < 0.05) and neutrophil-related markers (r = 0.925, p < 0.05) in NECRS while exhibiting broader cytokine correlations in ECRS (p < 0.05). Conclusions: Sinonasal HIF expression in CRS varies according to OSA risk and CRS endotype. OSA-associated hypoxic stress preferentially influences HIF-2α expression in NECRS, whereas this effect is attenuated in ECRS, likely due to the dominance of local type 2 inflammatory signaling.