Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis.
Satoshi WatanabeNikolay S MarkovZiyan LuRaul Piseaux AillonSaul SoberanesConstance E RunyanZiyou RenRogan A GrantMariana M HerreriasHiam Abdala-ValenciaYuliya PolitanskaKiwon NamLango SichizyaHermon G KihshenNikita JoshiAlexandra C McQuattie-PimentelKatherine A GrunerManu JainJacob I SznajderRichard I MorimotoPaul A ReyfmanCara J GottardiG R Scott BudingerAlexander V MisharinPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- pulmonary fibrosis
- induced apoptosis
- small molecule
- cell cycle arrest
- young adults
- stem cells
- multiple sclerosis
- endoplasmic reticulum stress
- immune response
- skeletal muscle
- type diabetes
- dendritic cells
- endothelial cells
- oxidative stress
- genome wide
- dna methylation
- adipose tissue
- mesenchymal stem cells
- childhood cancer
- copy number
- wound healing
- peripheral blood
- amino acid