IL-33/ST2信号在特发性肺纤维化中的作用及分子机制

Idiopathic pulmonary fibrosis (IPF), the most common form of the idiopathic interstitial pneumonias, is a chronic, progressive, irreversible, and usually lethal lung disease of unknown cause. Interleukin-33 (IL-33) was recently identified as the ligand for the then orphan receptor ST2 (also known as IL-1RL1). Binding of IL-33 to ST2 homodimers activates a cascade of signalling events leading to the activation of NF-kB and several MAPKs. IL-33 has been reported to have a pathogenic role in several inflammatory diseases. Our preliminary results demonstrated anti-IL-33 antibody can prevent the development of pulmonary fibrosis in a mouse model. In this project, we will evaluate the role of IL-33 in a murine model of IPF. We will investigate that the expression of IL-33 and its receptor, ST2, in the lung of mice during bleomycin-induced IPF, and administration of a blocking anti-IL-33 antibody, or ST2, or IL-33 shRNA in mice of IPF inhibits the onset and severity of pulmonary fibrosis. This study will help to elucidate that IL-33 plays a pivotal role in the pathogenesis of IPF and provide new ideas that blockade of IL-33 may be a new therapeutic strategy for pulmonary fibrosis.

特发性肺纤维化(IPF)是一种进行性的、不可逆的致死性慢性肺间质纤维化疾病。其发病机制尚未完全阐明，缺乏有效的疗法。IL-33是一种新发现的前炎症因子，能诱导T细胞、巨噬细胞和中性粒细胞等产生多种炎症因子，介导MAPK信号通路调节TGF-β。我们预实验显示，在博莱霉素(BLM)诱导的小鼠肺纤维化模型的肺组织中IL-33及其受体ST2高表达，抗IL-33能减轻小鼠肺纤维化症状，提示IL-33在IPF中起重要的作用。本项目用自主制备的抗IL-33、IL-33 shRNA、ST2蛋白，研究它们对小鼠肺纤维化、临床症状和免疫功能等的影响。本项目将有助于阐明IL-33/ST2在IPF发病中的作用机制，为IPF的防治提供新的思路。

特发性肺纤维化(IPF)是一种进行性的、不可逆的致死性慢性肺间质纤维化疾病。其发病机制尚未完全阐明，缺乏有效的疗法。IL-33是一种新发现的前炎症细胞因子，能诱导T细胞、巨噬细胞和中性粒细胞等产生多种炎症因子。本项目建立了博莱霉素(BLM)诱导的小鼠肺纤维化模型，发现小鼠模型中IL-33和ST2表达增加；用抗IL-33、IL-33 shRNA和慢病毒介导ST2分别注射肺纤维化模型小鼠，发现它们对小鼠肺部炎症与纤维化、临床症状等均有抑制作用，研究发现它们主要通过抑制前炎症细胞因子的表达，而促进抗纤维化细胞因子的释放起作用。本项目的完成为IPF的防治提供了新的思路和实验依据。本项目已发表SCI收录论文2篇，在投2篇，在写1篇。已发表国内核心期刊论文1篇。已申请国家发明专利1项。