Study On The Effects Of Hypoxia-inducible Factor 1α On Nasal Mucosa Inflammation And Remodeling In Allergic Rhinitis

Part Ⅰ. The establishment and evaluation of acute and chronic mice models with allergic rhinitisObjective To develop acute and chronic mice models with allergic rhinitis (AR).Methods An acute animal model of AR was developed by repeated nasal challenge with ovalbumin (OVA) in sensitized BALB/c mice. To develop a chronic mice model with AR, these OVA-challenged mice were subsequently received intranasal challenge three times a week for 14 weeks. These acute and chronic mice models with AR were assessed by nasal symptoms after OVA challenge, histopathological changes in nasal mucosa (HE, AB-PAS and Masson staining), and OVA-specific IgE levels in sera (ELISA).Results Inflammatory responses to OVA challenge, including nasal symptoms, inflammatory cell infiltration, eosinophil recruitment and up-regulation of serum OVA-specific IgE levels were present in the acute and chronic mice models with AR. Moreover, the number of goblet cells and the percentage area of collagen deposition were both improved significantly in the nasal mucosa of chronic mice model with AR.Conclusion We have successfully established acute and chronic mice models with AR and proved long-term allergen challenge may result in main features of remodeling in the nasal mucosa.Part Ⅱ. Effects of HIF-1α on nasal mucosa inflammation in an acute mice model with allergic rhinitisObjective To elucidate the role of hypoxia-inducible factor 1α (HIF-1α) in an acute mice models with AR.Methods Mice were pretreated with the HIF-1αnhibitor 2-methoxyestradiol (2ME2) or the HIF-1α inducer cobalt chloride (CoCl2) in an established AR murine model using OVA-sensitized BALB/c mice. HIF-1α and vascular endothelial growth factor (VEGF) expression in nasal mucosa was measured and multiple parameters of allergic responses were evaluated.Results HIF-1α and VEGF levels were locally up-regulated in nasal mucosa during AR. Inflammatory responses to OVA challenge, including nasal symptoms, inflammatory cell infiltration, eosinophil recruitment, up-regulation of IL-4 and IL-5 levels in nasal lavage fluid, and serum OVA-specific IgE levels were present in the OVA-challenged mice.2ME2 effectively inhibited HIF-1α and VEGF expression and attenuated the inflammatory responses. Stabilization of HIF-1αy CoCl2 facilitated nasal allergic inflammation. HIF-1α protein levels in nasal airways correlated with the severity of AR in mice.Conclusion HIF-la is intimately involved in the pathogenesis of nasal allergies, and the inhibition of HIF-1α may be useful as a novel therapeutic approach for AR.Part Ⅲ. Effects of HIF-la on nasal mucosa inflammation and remodeling in a chronic mice model with allergic rhinitisObjective To investigate the effects of HIF-la on nasal mucosa inflammation and remodeling in a chronic mice model with AR. The role of HIF-la mediation on the expression of VEGF, FGF-2 and TGF-β1 in allergic inflammation was also evaluated.Methods BALB/c mice were pretreated with 2ME2 or CoCl2 in a chronic animal model with AR. HIF-la, VEGF, FGF-2 and TGF-β1expression in nasal mucosa was measured. Multiple parameters of allergic responses, together with histopathological changes of nasal remodeling were evaluated.Results HIF-la level was locally up-regulated in the nasal mucosa of chronic AR mouse model associated with significant inflammatory responses to OVA challenge. Features of remodeling in the nasal mucosa, including significant goblet cell hyperplasia, collagen deposition and epithelial damage were present in these long-term OVA-challenged mice.2ME2 effectively inhibited HIF-la expression and reduced the nasal mucosa inflammation and remodeling. Long-term CoCl2 pretreatment did not produce marked changes in HIF-la expression as well as nasal mucosa inflammation and remodeling. HIF-la protein level was positively correlated with the expression of VEGF, FGF-2 and TGF-β1in acute and chronic mice models with AR.Conclusion These findings indicate that HIF-1α is directly involved in the development of nasal inflammation and remodeling during AR. Long-term HIF-la inhibition can attenuate antigen-induced nasal remodeling and the mechanism may be related to the downregulation of VEGF, FGF-2 and TGF-β1.