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
Genetic studies with mouse models have shown that fibroblast growth factor receptor 2-Ⅲb（FGFR2-Ⅲb）plays crucial roles in lung development and differentiation. To evaluate the effect of FGFR2-Ⅲb in pig lung develo...Genetic studies with mouse models have shown that fibroblast growth factor receptor 2-Ⅲb（FGFR2-Ⅲb）plays crucial roles in lung development and differentiation. To evaluate the effect of FGFR2-Ⅲb in pig lung development, we employed somatic cell nuclear transfer（SCNT） technology to generate transgenic pig fetuses overexpressing the transmembrane（dn FGFR2-Ⅲb-Tm） and soluble（dn FGFR2-Ⅲb-HFc） forms of the dominant-negative human FGFR2-Ⅲb driven by the human surfactant protein C（SP-C） promoter,which was specifically expressed in lung epithelia. Eight dn FGFR2-Ⅲb-Tm transgenic and twelve dn FGFR2-Ⅲb-HFc transgenic pig fetuses were collected from three and two recipient sows, respectively.Repression of FGFR2-Ⅲb in lung epithelia resulted in smaller lobes and retardation of alveolarization in both forms of dn FGFR2-Ⅲb transgenic fetuses. Moreover, the dn FGFR2-Ⅲb-HFc transgenic ones showed more deterioration in lung development. Our results demonstrate that disruption of FGFR2-Ⅲb signaling in the epithelium impedes normal branching and alveolarization in pig lungs, which is less severe than the results observed in transgenic mice. The dn FGFR2-Ⅲb transgenic pig is a good model for the studies of blastocyst complementation as well as the mechanisms of lung development and organogenesis.展开更多
Influenza virus (IAV)infection is a major cause of severe respiratory illness that affects almost every country in the world.IAV infections result in respiratory illness and even acute lung injury and death,but the un...Influenza virus (IAV)infection is a major cause of severe respiratory illness that affects almost every country in the world.IAV infections result in respiratory illness and even acute lung injury and death,but the underlying mechanisms responsible for IAV pathogenesis have not yet been fully elucidated.In this study,the basic fibroblast growth factor 2 (FGF2)level was markedly increased in H1N1 virus-infected humans and mice.FGF2,which is predominately derived from epithelial cells,recruits and activates neutrophils via the FGFR2-PI3K-AKT-NFKB signaling pathway.FGF2 depletion or knockout exacerbated influenzaassociated disease by impairing neutrophil recruitment and activation.More importantly,administration of the recombinant FGF2 protein significantly aUeviated the severity of IAV-induced lung injury and promoted the survival of IAV-infected mice.Based on the results from experiments in which neutrophils were depleted and adoptively transferred,FGF2 protected mice against IAV , infection by recruiting neutrophils.Thus,FGF2 plays a critical role in preventing IAV-induced lung injury,and FGF2 is a promising potential therapeutic target during IAV infection.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.
基金supported by grants from the National Natural Science Foundation of China(Nos.81570402 and 31701283)the National Key R&D Program of China(2017YFC1103701 and 2017YFC1103702)+3 种基金the Jiangsu Key Laboratory of Xenotransplantation(BM2012116)the Sanming Project of Medicine in Shenzhen(SZSM201412020)the Fund for High Level Medical Discipline Construction of Shenzhen(2016031638)the Shenzhen Foundation of Science and Technology(JCYJ20160229204849975 and GCZX2015043017281705)
文摘Genetic studies with mouse models have shown that fibroblast growth factor receptor 2-Ⅲb（FGFR2-Ⅲb）plays crucial roles in lung development and differentiation. To evaluate the effect of FGFR2-Ⅲb in pig lung development, we employed somatic cell nuclear transfer（SCNT） technology to generate transgenic pig fetuses overexpressing the transmembrane（dn FGFR2-Ⅲb-Tm） and soluble（dn FGFR2-Ⅲb-HFc） forms of the dominant-negative human FGFR2-Ⅲb driven by the human surfactant protein C（SP-C） promoter,which was specifically expressed in lung epithelia. Eight dn FGFR2-Ⅲb-Tm transgenic and twelve dn FGFR2-Ⅲb-HFc transgenic pig fetuses were collected from three and two recipient sows, respectively.Repression of FGFR2-Ⅲb in lung epithelia resulted in smaller lobes and retardation of alveolarization in both forms of dn FGFR2-Ⅲb transgenic fetuses. Moreover, the dn FGFR2-Ⅲb-HFc transgenic ones showed more deterioration in lung development. Our results demonstrate that disruption of FGFR2-Ⅲb signaling in the epithelium impedes normal branching and alveolarization in pig lungs, which is less severe than the results observed in transgenic mice. The dn FGFR2-Ⅲb transgenic pig is a good model for the studies of blastocyst complementation as well as the mechanisms of lung development and organogenesis.
基金funding from the National High Technology Research and Development Program of China (SS2015AA020924)the National Natural Science Foundation of China (81771700)+2 种基金the Ministry of Science and Technology of China (2013ZXI0004003 and SS2012AA020905)the National Major Research and Development Program (2016YFA0502203 and 2017YFC1200800)P.Y.was supported by the Beijing Nova Program (Z141107001814054).
文摘Influenza virus (IAV)infection is a major cause of severe respiratory illness that affects almost every country in the world.IAV infections result in respiratory illness and even acute lung injury and death,but the underlying mechanisms responsible for IAV pathogenesis have not yet been fully elucidated.In this study,the basic fibroblast growth factor 2 (FGF2)level was markedly increased in H1N1 virus-infected humans and mice.FGF2,which is predominately derived from epithelial cells,recruits and activates neutrophils via the FGFR2-PI3K-AKT-NFKB signaling pathway.FGF2 depletion or knockout exacerbated influenzaassociated disease by impairing neutrophil recruitment and activation.More importantly,administration of the recombinant FGF2 protein significantly aUeviated the severity of IAV-induced lung injury and promoted the survival of IAV-infected mice.Based on the results from experiments in which neutrophils were depleted and adoptively transferred,FGF2 protected mice against IAV , infection by recruiting neutrophils.Thus,FGF2 plays a critical role in preventing IAV-induced lung injury,and FGF2 is a promising potential therapeutic target during IAV infection.
