Hypoxia induces the production of epithelial-derived cytokines in eosinophilic chronic rhinosinusitis with nasal polyps

Background: Hypoxia plays a significant role in the pathogenesis of chronic rhinosinusitis (CRS). However, the role and mechanism of hypoxia in the type 2 immune response in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remain unclear.Methods: The expression of hypoxia-inducible factor-1a (HIF-1a) and epithelial-derived cytokines (EDCs), including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), was detected in nasal polyps via immunohistochemical analysis. The relationship between HIF-1a and EDCs was also elucidated using Pearson's correlation. Moreover, primary human nasal epithelial cells (HNECs) and a mouse model of ECRSwNP were employed to elucidate the role and mechanism of hypoxia in type 2 immune responses.Results: HIF-1a, IL-25, IL-33, and TSLP expression levels were upregulated in the non-ECRSwNP and ECRSwNP groups compared with the control group, with the ECRSwNP group having the highest HIF-1a and EDC expression levels. Additionally, HIF-1a was positively correlated with IL-25 and IL-33 in the ECRSwNP group. Meanwhile, treatment with a HIF-1a inhibitor, PX-478, inhibited the hypoxia-induced increase in the mRNA and protein expression of EDCs and type 2 cytokines in HNECs. Similarly, in vivo, PX-478 inhibited EDC expression in the sinonasal mucosa of mice with ECRSwNP.Conclusions: Hypoxia induces EDC expression by upregulating HIF-1a levels, thereby promoting type 2 immune responses and the development of ECRSwNP. Hence, targeting HIF-1a may represent an effective therapeutic strategy for ECRSwNP.