px-478 and Rhinitis

Hypoxia is involved in inflammation and immune response; however, its role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) is not fully understood. We aimed to investigate the mechanisms by which hypoxia disrupts the nasal epithelial barrier in CRSwNP.. The expression of hypoxia-inducible factor-1α (HIF-1α), protein tyrosine phosphatase non-receptor type 2 (PTPN2), and tight junction (TJ) components (claudin-4, occludin, and ZO-1) was detected in nasal polyps using immunohistochemistry, western blotting, and qRT-PCR. Primary human nasal epithelial cells (HNECs), BEAS-2B cells, and an eosinophilic CRSwNP (Eos CRSwNP) mouse model were used to explore the potential mechanisms by which hypoxia disrupts the nasal epithelial barrier.. HIF-1α expression in the non-Eos and Eos CRSwNP groups was higher than in the control group, and the expression of PTPN2 and TJs in the non-Eos and Eos CRSwNP groups were lower than those in the control group. Hypoxia decreased the expression of PTPN2 and TJs and increased epithelial cell permeability in HNECs, which was blocked by the HIF-1α inhibitor PX-478. PTPN2 overexpression inhibited hypoxia-induced downregulation of TJ expression in BEAS-2B cells, whereas PTPN2-knockdown aggravated the effects of hypoxia. In the Eos CRSwNP mouse model, both PX-478 and PTPN2 overexpression reduced the formation of nasal polypoid lesions, permeability of the nasal epithelium, and restored TJ expression.. Our data indicate that hypoxia-induced HIF-1α downregulates TJ expression by inhibiting PTPN2, thereby disrupting the nasal epithelial barrier and promoting CRSwNP development. HIF-1α and PTPN2 may be potential targets for the treatment of CRSwNP.

Topics: Animals; Chronic Disease; Epithelial Cells; Humans; Hypoxia; Mice; Nasal Mucosa; Nasal Polyps; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Rhinitis; Sinusitis

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.. The expression of hypoxia-inducible factor-1α (HIF-1α) 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-1α 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.. HIF-1α, 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-1α and EDC expression levels. Additionally, HIF-1α was positively correlated with IL-25 and IL-33 in the ECRSwNP group. Meanwhile, treatment with a HIF-1α 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.. Hypoxia induces EDC expression by upregulating HIF-1α levels, thereby promoting type 2 immune responses and the development of ECRSwNP. Hence, targeting HIF-1α may represent an effective therapeutic strategy for ECRSwNP.

Topics: Animals; Chronic Disease; Cytokines; Humans; Hypoxia; Interleukin-33; Mice; Nasal Polyps; Rhinitis; Sinusitis; Thymic Stromal Lymphopoietin