髓样分化蛋白-2在屋尘螨诱导炎症和哮喘中的作用和机制研究

Chronic airway inflammation induced by house dust mite (HDM) is one of the main pathological factors for the development of asthma. However, the underlying mechanism of HDM and allergens induced inflammatory respnse is not clear. Myeloid differentiation-2 (MD-2) plays an importment role on LPS-mediated TLR4 pathway. Studies have shown that toll like receptor (TLR) 4 participated in inflammation-mediated asthma, yet there is no report about MD-2 involved in the development of asthma. In our previous work, we found that L2H21, a MD-2 specific inhibitor, obviously attenuated HDM-induced asthma. Meanwhile, there is no direct bonding between HDM allergens, Der P 1/2, and TLR4. Based on these results, we have the hypothesis that ①MD-2 maybe directly binding with Der P 1 and activates TLR4 inflammatory pathway; ②MD-2 plays an important role in the development and progression of asthma. Thus a series of studies are designed to test and confirm our assumption, including, ①to elucidate the role and mechanism of MD2 and its pathway on the HDM, Der P 1/2-induced inflammatory response; ②to validate the role of MD-2 on the development of asthma induced by HDM or Der P 1/2 in MD2-/- mice. We will confirm that MD-2 have an important role on the development of asthma and provide a new target for treating asthma.

屋尘螨（HDM）引起的气道慢性炎症是哮喘的主要病理因素之一，但HDM及其变应原如何激活炎症反应尚不完全清晰。髓样分化蛋白（MD）2是介导内毒素LPS激活TLR4的重要蛋白。有研究表明TLR4激活与HDM哮喘相关，但MD2在哮喘中的作用尚无报道。课题组前期工作中发现口服特异性的MD2小分子抑制剂L2H21可以明显缓解HDM诱导的哮喘；同时，HDM变应原Der P 1/2与TLR4并无直接结合。我们假设：MD2可能直接结合Der P 1/2，激活TLR4炎症反应，在HDM哮喘发生发展中有着重要作用。本项目中，我们拟在分子和细胞层面，阐明MD2及其下游信号在HDM、Der P 1/2诱导炎症反应中的作用和分子机制；利用MD2-/-小鼠，确证MD2在HDM和Der P 1/2诱导的哮喘发展中的作用。项目实施将明确 MD2 在哮喘发生发展中的重要作用，为哮喘防治提供新靶点。

支气管哮喘(简称哮喘)是一种反复发作的慢性炎症性呼吸系统疾病。髓样分化蛋白2（MD2）是TLR4的重要辅助蛋白，在TLR4识别LPS的过程中起重要的介导作用。已经有报道指出TLR4介导哮喘疾病的发生发展，那么MD2在哮喘发病中的作用尚无报道。因此我们采用卵清蛋白OVA致敏和激发诱导小鼠哮喘，并且采用了我们自主设计合成的MD2小分子抑制剂L6H21以及天然产物黄芩素（MD2抑制剂）为小分子探针在动物层面发现L6H21和黄芩素能够通过靶向MD2缓解OVA诱导的小鼠气道粘液高分泌、炎症细胞浸润以及气道炎症反应；在细胞层面黄芩素能够抑制细胞因子TNF-a诱导的NF-κB信号通路的激活和炎症细胞因子的表达。同时我们在细胞和动物层面也发现天然产物荜茇酰胺通过NF-κB信号通路缓解OVA诱导的哮喘及气道炎症反应。该项目的实施，确证了MD2在介导哮喘发病中的作用，其小分子抑制剂能够作为临床治疗哮喘的潜在候选药物。