Midkine/MCP-1信号在可吸入颗粒物加重胸膜下区肺纤维化中的作用及其机制研究

近20年我国特发性肺纤维化（IPF）发病率明显增高，研究已经认为吸烟、空气污染与IPF的加重明显相关。吸烟及污染的空气中含有大量的可吸入颗粒物，因此，颗粒物的吸入与IPF的关系非常值得探究。IPF的一个显著特点是胸膜下区肺纤维化。我们的预实验发现香烟烟雾、PM2.5吸入都明显加重小鼠肺纤维化尤其胸膜下区域。巨噬细胞是肺纤维化的重要参与细胞，它受巨噬细胞趋化因子MCP-1的驱动而聚集。我们通过抗体芯片筛选发现，胸膜间皮细胞特异性表达一种叫做Midkine的生长因子，PM2.5可以使它明显上调，它又可上调MCP-1，从而导致巨噬细胞向胸膜下区聚集，这可能是可吸入颗粒物加重胸膜下区的肺纤维化的重要原因。因此，本项目拟从细胞、动物及临床标本等方面展开研究，回答Midkine/MCP-1信号在胸膜下区肺纤维化发生中的价值，为疾病的防治提供新的可能的靶点。

In the past 20 years, the morbility of idiopathic pulmonary fibrosis (IPF) in China increased significantly. It was reported that cigarette smoke and air pollution are the most important risk factors for the exacerbation of IPF. There are a lot of inhalable particulate matters contaminated in cigarettes and polluted air. Therefore, it is very necessary to explore the relationship between the inhalation of particulate matters and IPF. One of the remarkable features of IPF is sub-pleural distribution of pulmonary fibrosis. Our preliminary experiments found, that inhalation of cigarette smoke or PM2.5 aggravated bleomycin induced mouse pulmonary fibrosis, especially sub-pleural fibrosis. Macrophage is very important in the pathogenesis of pulmonary fibrosis, it gathered at sub-pleural area by chemotaxis which mediated by macrophage chemoattractant protein-1 (MCP-1). By Antibody microarrays, we found a novel growth factor named Midkine, which specifically expressed in pleural mesothelial cells, and up-regulated by PM2.5 exposure. Midkine can up-regulate MCP-1, which induced gathering of macrophages at sub-pleural area, and maybe contribute to inhalable particulate matter aggravate sub-pleural pulmonary fibrosis. Therefore, we plan to investigate the role of Midkine/MCP-1 signal pathway in inhalable particulate matter aggravate sub-pleural pulmonary fibrosis with in vitro, in vivo and clinic studies, this project will provide novel target for the prevention and treatment of idiopathic pulmonary fibrosis.