Idiopathic pulmonary fibrosis(IPF)is a progressive disease lacking effective therapy.Metformin,an antidiabetic medication,has shown promising therapeutic properties in preclinical fibrosis models;however,its precise c...Idiopathic pulmonary fibrosis(IPF)is a progressive disease lacking effective therapy.Metformin,an antidiabetic medication,has shown promising therapeutic properties in preclinical fibrosis models;however,its precise cellular targets and associated mechanisms in fibrosis resolution remain incompletely defined.Most research on metformin’s effects has focused on mesenchymal and inflammatory responses with limited attention to epithelial cells.In this study,we utilized Sftpc lineage-traced and Fgfr2b conditional knockout mice,along with BMP2/PPARγand AMPK inhibitors,to explore metformin’s impact on alveolar epithelial cells in a bleomycin-induced pulmonary fibrosis model and cell culture.We found that metformin increased the proliferation and differentiation of alveolar type 2(AT2)cells,particularly the recently identified injury-activated alveolar progenitors(IAAPs)-a subpopulation characterized by low SFTPC expression but enriched for PD-L1.Single-cell RNA sequencing revealed a reduction in apoptosis among mature AT2 cells.Interestingly,metformin’s therapeutic effects were not significantly affected by BMP2 or PPARγinhibition,which blocked the lipogenic differentiation of myofibroblasts.However,Fgfr2b deletion in Sftpc lineage cells significantly impaired metformin’s ability to promote fibrosis resolution,a process linked to AMPK signaling.In conclusion,metformin alleviates fibrosis by directly activating AT2 cells,especially the IAAPs,through a mechanism that involves AMPK and FGFR2b signaling,but is largely independent of BMP2/PPARγpathways.展开更多
基金supported by the Discipline Cluster of Oncology of Wenzhou Medical University,China(Grant No.Z1-2023004 to Jin-San Zhang)Zhejiang Province Public Welfare Fund Project,China(Grant No.LY24H050003 to Jin-San Zhang)the National Natural Science Foundation of China(Grant No.82170017 to Chengshui Chen).
文摘Idiopathic pulmonary fibrosis(IPF)is a progressive disease lacking effective therapy.Metformin,an antidiabetic medication,has shown promising therapeutic properties in preclinical fibrosis models;however,its precise cellular targets and associated mechanisms in fibrosis resolution remain incompletely defined.Most research on metformin’s effects has focused on mesenchymal and inflammatory responses with limited attention to epithelial cells.In this study,we utilized Sftpc lineage-traced and Fgfr2b conditional knockout mice,along with BMP2/PPARγand AMPK inhibitors,to explore metformin’s impact on alveolar epithelial cells in a bleomycin-induced pulmonary fibrosis model and cell culture.We found that metformin increased the proliferation and differentiation of alveolar type 2(AT2)cells,particularly the recently identified injury-activated alveolar progenitors(IAAPs)-a subpopulation characterized by low SFTPC expression but enriched for PD-L1.Single-cell RNA sequencing revealed a reduction in apoptosis among mature AT2 cells.Interestingly,metformin’s therapeutic effects were not significantly affected by BMP2 or PPARγinhibition,which blocked the lipogenic differentiation of myofibroblasts.However,Fgfr2b deletion in Sftpc lineage cells significantly impaired metformin’s ability to promote fibrosis resolution,a process linked to AMPK signaling.In conclusion,metformin alleviates fibrosis by directly activating AT2 cells,especially the IAAPs,through a mechanism that involves AMPK and FGFR2b signaling,but is largely independent of BMP2/PPARγpathways.
