低氧诱导因子1α在变应性鼻炎鼻黏膜炎症及组织重塑中的作用研究

Hypoxia-inducible factor 1 (HIF-1) is an important transcriptional activator that mediates transcriptional response to hypoxia in organism. The accumulation and activation of HIF-1α protein plays a crucial role in cellular adaptation to low oxygen availability and it has also been found to contribute to allergic in?ammation. However, the biochemical mechanisms leading to the activation of HIF-1α protein in nasal mucosa epithelial cells and the effects of HIF-1α on nasal mucosa inflammation and remodeling in the allergic rhinitis（AR）are not clear.Combining with relative research progress at home and abroad，we hypothesize that HIF-1α is activated in nasal mucosa epithelial cells and is essential for the development of nasal mucosa inflammation and remodeling in AR. Therefore, we want to investigate the signaling networks involved in HIF-1α activation and the effects of HIF-1α mediation on the expression of VEGF,bFGF and TGF-β1 in allergic in?ammation by using HIF-1α siRNA transfection and intervention agents. Furthermore, the results will be validated by animal models of AR, which could verify that HIF-1α inhibition should attenuate the development of AR. The completion of our study may conform that HIF-1α could be a potential novel target for AR treatment and be helpful in getting a better understanding of the pathogenesis of allergic airway inflammation.

低氧诱导因子1（HIF-1）作为介导机体缺氧反应的重要转录因子，其α亚基的活化是细胞缺氧应答的关键环节，并参与变应性炎症反应的调控，但HIF-1α在变应性鼻炎（AR）鼻黏膜上皮细胞中活化的分子机制及HIF-1α干预对鼻黏膜炎症及组织重塑的影响，目前尚不清楚。结合相关研究进展，本课题设想HIF-1α在AR鼻黏膜上皮细胞活化，并对鼻黏膜炎症及组织重塑起着重要调节作用，因此本课题拟利用siRNA及不同的干预剂来阻断HIF-1α的表达，探讨变应性炎症状态下HIF-1α在鼻黏膜上皮细胞活化的信号传导通路调控机制，以及HIF-1α调控对VEGF、bFGF和TGF-β1表达的影响，并通过动物模型来加以验证，从而证实HIF-1α抑制对AR进展的干预作用。这项研究的完成，有可能为深入理解呼吸道变应性疾病的发病机制及AR的治疗提供新思路。

最新的研究显示低氧诱导因子1α（HIF-1α）参与了变应性炎症反应的调控，但HIF-1α在变应性鼻部炎症及组织重塑中的调控作用及其对VEGF、FGF-2和TGF-β1等生长因子的影响并不清楚。首先本课题组利用HIF-1α shRNA及不同的干预剂来阻断HIF-1α的表达，探讨变应性炎症状态下HIF-1α在原代鼻黏膜上皮细胞活化的调控机制。我们发现变应原（粉尘螨颗粒）通过激活PI3K/Akt/HIF-1α 信号通路来诱导鼻黏膜上皮细胞分泌VEGF、FGF-2和TGF-β1等生长因子。接下来我们建立了变应性鼻炎（AR）小鼠急性和慢性模型，且AR慢性模型具备了鼻黏膜组织重塑的主要特征。对AR小鼠模型应用不同的干预剂进行预处理，探讨HIF-1α调控对VEGF、bFGF和TGF-β1表达的影响，同时评估多项反映鼻部变应性炎症反应的指标以及鼻黏膜重塑的组织病理学表现。研究发现PI3K/Akt/HIF-1α 信号通路参与了变应原刺激鼻黏膜所致的炎症反应及其对生长因子表达的调控，AR小鼠模型中HIF-1α水平与鼻黏膜炎症和组织重塑程度密切相关。长期的HIF-1α抑制可有效改善持续变应原刺激所致的鼻黏膜组织重塑，其机制与下调VEGF、FGF-2和TGF-β1的水平有关。HIF-1α在变应性鼻部炎症发生和持续进程中起到重要作用，并且通过直接和间接的途径调控着VEGF、bFGF和TGF-β1等表达，提示HIF-1α可能是干预鼻黏膜变应性炎症及组织重塑的重要靶点。