特发性肺纤维化（IPF）是一种因慢性进行性肺功能丧失最终导致病人死亡的严重疾病，其病理机制尚未探明。虽然炎症反应是IPF一个重要特点，但是巨噬细胞是否参与调控IPF尚不清楚。我们前期研究不仅发现巨噬细胞特异性p38alpha MAPK敲除小鼠和巨噬细胞敲除小鼠肺纤维化明显减弱，而且首次证明蛋白激酶p38alpha MAPK是调控M2型巨噬细胞极化和炎症因子CCL17/22、Fizz-1产生的关键分子。基于坚实的前期研究结果，本研究将系统地阐明巨噬细胞在IPF中的作用特点；探明p38alpha MAPK促进M2型巨噬细胞极化介导IPF的分子病理机制；评价p38alpha MAPK作为治疗IPF的新型药物靶标作用。最终阐明p38alpha MAPK通过促进M2型巨噬细胞极化，释放CCL17/22和Fizz-1等炎症因子，介导IPF病理损伤的分子机制，为治疗肺纤维化提供一个潜在的新型药物靶标。

Idiopathic pulmonary fibrosis (IPF) is a fatal disease caused by a chronic progressive decline in lung function. The molecular and pathological mechanisms for IPF are still unknown. Although pulmonary inflammation can lead to IPF, the role of alveolar macrophage in IPF hasn’t been defined yet. Based on our supporting data, we not only found that both macrophage-specific p38alpha MAPK knockout mice and macrophage depletion mice displayed an attenuated pulmonary fibrosis, but also prove that p38alpha MAPK played a critical role in modulation of M2 macrophage polarization and CCL17/22 and Fizz-1 production. Therefore, we conclude that M2 macrophage polarization is necessary for mediating IPF. Based on our solid supporting data and novel hypothesis, we will comprehensively describe it by 4 specific aims: (1) To determine the role of macrophage in IPF; (2) To determine the necessity and sufficiency for p38alpha MAPK in M2 macrophage polarization and IPF; (3) To determine whether p38alpha MAPK-induced CCL17, CCL22 and Fizz-1 contribute to idiopathic pulmonary fibrosis; (4) To determine whether inhibiting p38alpha MAPK can ameliorate IPF. Take together, our studies will not only interrogate the molecular pathological mechanisms that M2 macrophage is necessary for mediating pulmonary fibrosis via p38alpha MAPK-mediated signal transduction, but also provide a scientific basis for development of novel drug targets for therapeutic intervention of IPF.