The factors that determine fibrosis progression or normal tissue repair are largely unknown.We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition(EMT)in human alveolar epithel...The factors that determine fibrosis progression or normal tissue repair are largely unknown.We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition(EMT)in human alveolar epithelial type Il(ATIl)cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signaling.Here,we report that liver kinase B1(LKB1)inactivation in ATIl cells inhibits autophagy and induces EMT as a conse-quence.In IPF lungs,this is caused by the down-regulation of CAB39L,a key subunit within the LKB1 complex.3D co-cultures of ATIl cells and MRC5 lung fibroblasts coupled with RNA sequencing(RNA-seq)confirmed that paracrine signaling between LKB1-depleted ATIl cells and fibroblasts augmented myofibroblast differentiation.Together,these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATIl cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.展开更多
Progressive lung fibrosis is characterized by dysregulated extracellular matrix(ECM)homeostasis.Understand-ing of disease pathogenesis remains limited and has prevented the development of effective treatments.While an...Progressive lung fibrosis is characterized by dysregulated extracellular matrix(ECM)homeostasis.Understand-ing of disease pathogenesis remains limited and has prevented the development of effective treatments.While an abnormal wound-healing response is strongly implicated in lung fibrosis initiation,factors that determine why fi-brosis progresses rather than regular tissue repair occur are not fully explained.Within human lung fibrosis,there is evidence of altered epithelial and mesenchymal populations as well as cells undergoing epithelial-mesenchymal transition(EMT),a dynamic and reversible biological process by which epithelial cells lose their cell polarity and down-regulate cadherin-mediated cell-cell adhesion to gain migratory properties.This review will focus on the role of EMT and dysregulated epithelial-mesenchymal crosstalk in progressive lung fibrosis.展开更多
基金supported by the UK Medical Research Council(MR/S025480/1)the UK Academy of Medical Sciences/the Wellcome Trust Springboard Award(SBF002/1038)+2 种基金AAIR Charity.ZX and LY were supported by China Scholarship Council.YZ was supported by an Institute for Life Sciences PhD Studentship.JD was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK(FC001070)the UK Medical Research Council(FC001070)the Wellcome Trust(FC001070).
文摘The factors that determine fibrosis progression or normal tissue repair are largely unknown.We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition(EMT)in human alveolar epithelial type Il(ATIl)cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signaling.Here,we report that liver kinase B1(LKB1)inactivation in ATIl cells inhibits autophagy and induces EMT as a conse-quence.In IPF lungs,this is caused by the down-regulation of CAB39L,a key subunit within the LKB1 complex.3D co-cultures of ATIl cells and MRC5 lung fibroblasts coupled with RNA sequencing(RNA-seq)confirmed that paracrine signaling between LKB1-depleted ATIl cells and fibroblasts augmented myofibroblast differentiation.Together,these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATIl cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.
基金supported by the UK Medical Research Council(MR/S025480/1)the UK Academy of Medical Sciences/the Well-come Trust Springboard Award[SBF002\1038]LY and ZX were sup-ported by the China Scholarship Council.
文摘Progressive lung fibrosis is characterized by dysregulated extracellular matrix(ECM)homeostasis.Understand-ing of disease pathogenesis remains limited and has prevented the development of effective treatments.While an abnormal wound-healing response is strongly implicated in lung fibrosis initiation,factors that determine why fi-brosis progresses rather than regular tissue repair occur are not fully explained.Within human lung fibrosis,there is evidence of altered epithelial and mesenchymal populations as well as cells undergoing epithelial-mesenchymal transition(EMT),a dynamic and reversible biological process by which epithelial cells lose their cell polarity and down-regulate cadherin-mediated cell-cell adhesion to gain migratory properties.This review will focus on the role of EMT and dysregulated epithelial-mesenchymal crosstalk in progressive lung fibrosis.
