Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
Am J Respir Crit Care Med
; 203(6): 707-717, 2021 03 15.
Article
en En
| MEDLINE
| ID: mdl-32991815
ABSTRACT
Rationale Idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Accelerated aging, loss of epithelial progenitor cell function and/or numbers, and cellular senescence are implicated in the pathogenies of IPF.Objectives:
We sought to investigate the role of alveolar type 2 (AT2) cellular senescence in initiation and/or progression of pulmonary fibrosis and therapeutic potential of targeting senescence-related pathways and senescent cells.Methods:
Epithelial cells of 9 control donor proximal and distal lung tissues and 11 IPF fibrotic lung tissues were profiled by single-cell RNA sequencing to assesses the contribution of epithelial cells to the senescent cell fraction for IPF. A novel mouse model of conditional AT2 cell senescence was generated to study the role of cellular senescence in pulmonary fibrosis.Measurements and MainResults:
We show that AT2 cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of AT2 cells promotes progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation or senescence block fibrogenesis.Conclusions:
Senescence of AT2 cells is sufficient to drive progressive pulmonary fibrosis. Early attenuation of senescence-related pathways and elimination of senescent cells are promising therapeutic approaches to prevent pulmonary fibrosis.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Envejecimiento
/
Senescencia Celular
/
Fibrosis Pulmonar Idiopática
/
Células Epiteliales Alveolares
Tipo de estudio:
Prognostic_studies
Límite:
Aged
/
Aged80
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Am J Respir Crit Care Med
Asunto de la revista:
TERAPIA INTENSIVA
Año:
2021
Tipo del documento:
Article