原发性肺纤维化是临床上慢性、不可逆的高致死率间质性肺疾病。肺泡M2型巨噬细胞活化促进多胺合成及成纤维细胞增生在肺纤维化中起重要作用。磷脂酰肌醇-3-激酶（phosphatidylinositol-3-kinase，PI3K）参与细胞多种重要功能及信号转导。我们意外发现PI3K催化亚基p110δ突变促进肺纤维化并增加肺组织中巨噬细胞浸润，且引起巨噬细胞M2型分子（Arg1，Fizz1，Yim1）表达上调而M1型（iNOS)）表达下调。基于以上工作，我们将用IFNγ/LPS+IL-4联合诱导p110δ突变的巨噬细胞，明确p110δ突变促进M1向M2表型转换的重要性。鉴于STAT6/PGC-1β途径调控M2表型活化，我们将在细胞和整体水平研究p110δ突变如何诱导M1向M2转换。进一步在临床肺纤维化病人中明确p110δ突变与肺泡巨噬细胞M2活化的关系。揭示p110δ在肺纤维化中的重要作用和机制。

Idiopathic pulmonary fibrosis (IPF) is a progressively interstitial lung disease with high mortality. Activation of M2 alveolar macrophages，which promotes polyamines synthesis and fibroblast proliferation，play an key role in the development of IPF. Phosphatidylinositol-3-kinase (PI3K) involved in important function and signaling transduction in cells. We unexpectedly observed that p110δ mutation exacerbates bleomycin-induced pulmonary fibrosis and promotes macrophages infiltration in lung. Moreover, p110δ mutant significantly increase M2 marker (Arg1, Fizz1, Yim1) expressions whereas decrease M1 marker (iNOS) in macrophages. Based on previous work, we will stimulate p110δ mutant-macrophages with IFNγ/LPS+IL-4 to prove the importance of p110δ mutant in M1-M2 transition. Furthermore, since STAT6/PGC-1β signaling pathway regulates M2 activation, we will study the mechanism how p110δ mutant promote M1-M2 transition. Finally, we will confirm the association between p110δ mutant in patient with IPF and M2 activation.