丁酸盐通过靶向HDAC1影响RAGE/β-catenin轴改善激素抵抗型TDI哮喘模型气道炎症的分子机制

我们发现气道上皮RAGE/β-catenin轴在甲苯二异氰酸酯(TDI)激素抵抗型哮喘气道炎症中扮演着重要角色，然而其靶向调控途径及作用尚不清楚。短链脂肪酸(SCFAs)在肠-肺轴免疫调节中发挥重要桥梁作用，是近年关注热点，SCFAs对哮喘免疫调节也越来越受到重视。研究显示，SCFAs可以通过受体如GPR41、GPR43和抑制组蛋白去乙酰化酶（HDACs）途径参与哮喘炎症过程。预实验发现SCFAs尤其丁酸盐可减轻TDI气道炎症，改善气道屏障和上皮β-catenin分布，能降低RAGE表达。进一步发现丁酸盐可逆转TDI引起气道上皮HDAC1上调，却降低受体GPR41、GPR43表达。由此我们提出假设：丁酸盐通过靶向HDAC1影响RAGE/β-catenin轴改善TDI哮喘气道炎症。我们以气道上皮为主要研究对象，拟采用既有成熟模型，从体内、外实验验证上述假说。本研究将为哮喘精准治疗提供新思路。

We firstly found that the RAGE/β-catenin axis in airway epithelium plays an important role in airway inflammation in toluene diisocyanate (TDI) induced steriod-resistant asthma, but the pathway and function of targeted regulation are not clear. Short-chain fatty acids (SCFAs), as key gut bacterial metabolites, play an important role in the immune regulation of the gut lung axis, which has been a hot spot in recent years. More and more attention has been paid on the role of SCFAs in the pathegenisis of asthma. Research shows that SCFAs can participate in the inflammatory process of asthma through receptors such as gpr41, gpr43 and inhibition of histone acetylase (HDACs),however,its definite mechanisms remains unresolved..In our pre-experiment, SCFAs, especially butyrate,could alleviate airway inflammation, improve airway barrier and epithelial β-catenin distribution, and reduce RAGE expression. The further study showed that butyrate，similar to RAGE blockage could reverse the up regulation of HDAC1 induced by TDI, but decrease the receptor expression of GPR41and GPR43. Therefore, we speculate that butyrate could improve airway inflammation of TDI asthma by targeting HDAC1 to affect RAGE/ β-catenin axis..In order to verify the hypothesis in vivo and in vitro study, we will use airway epithelium as the main object of study, and use the mature model which have been set up in our lab. This study will provide a new way to expand the regulation mechanism of SCFAs on RAGE/β-catenin axis in airway inflammation.