Febuxostat Alleviates Allergic Rhinitis by Inhibiting Inflammation and Monocyte Adhesion in Human Nasal Epithelial Cells via Regulating KLF6

Abstract

Introduction. Febuxostat is a novel inhibitor of xanthine oxidase that suppresses cell adhesion molecules-mediated (CAMs) inflammation by activating KLF6. In this study, we explored the therapeutic function and potential mechanisms of febuxostat against allergic rhinitis (AR). Methods. We investigated the role of febuxostat through in vitro cell and in vivo animal experiments. Human nasal epithelial cells (hNECs) were cultured with histamine as an in vitro model. To establish the AR animal model, rats were exposed to ovalbumin. Rats were randomly grouped into control, model, 7.5 mg/kg febuxostat, and 15 mg/kg febuxostat groups. Results. In the in vitro study, we found significantly increased release of lactate dehydrogenase, elevated production of inflammatory factors and chemokines, and upregulated CAMs in histamine-treated hNECs. However, these results were significantly reversed for the 10 and 20 μM febuxostat treatments. The enhanced adhesion between hNECs and monocytes induced by histamine was dramatically repressed by febuxostat. In the vivo experiments, we observed that febuxostat ameliorated the increased sneezing times, the number of nose scratching episodes, and elevated HE pathological scores as well as alleviated the inflammation in nasal mucous tissues of AR mice. We found that KLF6, which was downregulated in histamine-treated hNECs, was significantly upregulated by febuxostat. The inhibitory effects of febuxostat on the expression levels of CAMs and adhesion between histamine-treated hNECs and monocytes were significantly abolished by the knockdown of KLF6. Conclusion. Febuxostat alleviates AR by inhibiting inflammation and monocyte adhesion in human nasal epithelial cells through the regulation of KLF6.