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1.
Nat Cell Biol ; 22(10): 1197-1210, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32989251

RESUMO

Alveolar epithelial regeneration is essential for recovery from devastating lung diseases. This process occurs when type II alveolar pneumocytes (AT2 cells) proliferate and transdifferentiate into type I alveolar pneumocytes (AT1 cells). We used genome-wide analysis of chromatin accessibility and gene expression following acute lung injury to elucidate repair mechanisms. AT2 chromatin accessibility changed substantially following injury to reveal STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways. Single-cell transcriptome analysis identified brain-derived neurotrophic factor (Bdnf) as a STAT3 target gene with newly accessible chromatin in a unique population of regenerating AT2 cells. Furthermore, the BDNF receptor tropomyosin receptor kinase B (TrkB) was enriched on mesenchymal alveolar niche cells (MANCs). Loss or blockade of AT2-specific Stat3, Bdnf or mesenchyme-specific TrkB compromised repair and reduced Fgf7 expression by niche cells. A TrkB agonist improved outcomes in vivo following lung injury. These data highlight the biological and therapeutic importance of the STAT3-BDNF-TrkB axis in orchestrating alveolar epithelial regeneration.


Assuntos
Células Epiteliais Alveolares/citologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lesão Pulmonar/prevenção & controle , Glicoproteínas de Membrana/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptor trkB/metabolismo , Regeneração , Fator de Transcrição STAT3/metabolismo , Células Epiteliais Alveolares/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Humanos , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Masculino , Glicoproteínas de Membrana/genética , Proteínas Tirosina Quinases/genética , Receptor trkB/genética , Fator de Transcrição STAT3/genética
2.
Am J Physiol Lung Cell Mol Physiol ; 311(6): L1062-L1075, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27694472

RESUMO

Alveolar epithelial regeneration is essential for resolution of the acute respiratory distress syndrome (ARDS). Although neutrophils have traditionally been considered mediators of epithelial damage, recent studies suggest they promote type II pneumocyte (AT2) proliferation, which is essential for regenerating alveolar epithelium. These studies did not, however, evaluate this relationship in an in vivo model of alveolar epithelial repair following injury. To determine whether neutrophils influence alveolar epithelial repair in vivo, we developed a unilateral acid injury model that creates a severe yet survivable injury with features similar to ARDS. Mice that received injections of the neutrophil-depleting Ly6G antibody had impaired AT2 proliferation 24 and 72 h after acid instillation, which was associated with decreased reepithelialization and increased alveolar protein concentration 72 h after injury. As neutrophil depletion itself may alter the cytokine response, we questioned the contribution of neutrophils to alveolar epithelial repair in neutropenic granulocyte-colony stimulating factor (G-CSF)-/- mice. We found that the loss of G-CSF recapitulated the neutrophil response of Ly6G-treated mice and was associated with defective alveolar epithelial repair, similar to neutrophil-depleted mice, and was reversed by administration of exogenous G-CSF. To approach the mechanisms, we employed an unbiased protein analysis of bronchoalveolar lavage fluid from neutrophil-depleted and neutrophil-replete mice 12 h after inducing lung injury. Pathway analysis identified significant differences in multiple signaling pathways that may explain the differences in epithelial repair. These data emphasize an important link between the innate immune response and tissue repair in which neutrophils promote alveolar epithelial regeneration.


Assuntos
Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares/patologia , Epitélio/patologia , Neutrófilos/patologia , Regeneração , Ácidos , Lesão Pulmonar Aguda/induzido quimicamente , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Anticorpos/farmacologia , Líquido da Lavagem Broncoalveolar , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/deficiência , Fator Estimulador de Colônias de Granulócitos/metabolismo , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Proteômica , Regeneração/efeitos dos fármacos , Síndrome do Desconforto Respiratório/patologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
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