Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis.
Proc Natl Acad Sci U S A
; 118(20)2021 05 18.
Article
em En
| MEDLINE
| ID: mdl-33972447
ABSTRACT
Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fibrose Pulmonar
/
Cicloexilaminas
/
Células Epiteliais Alveolares
/
Proteostase
/
Acetamidas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article