Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis

• DOI: 10.1073/pnas.2101100118
• Publication Date: 2021-05-10T21:19:04Z
• Authors: Satoshi Watanabe; Nikolay S. Markov; Ziyan Lu; Raul Piseaux Aillon; Saul Soberanes; Constance E. Runyan; Ziyou Ren; Rogan A. Grant; Mariana Maciel; Hiam Abdala-Valencia; Yuliya Politanska; Kiwon Nam; Lango Sichizya; Hermon G. Kihshen; Nikita Joshi; Alexandra C. McQu...; Katherine A. Gruner; Manu Jain; Jacob I. Sznajder; Richard I. Morimoto; Paul A. Reyfman; Cara J. Gottardi; G. R. Scott Budinger; Alexander V. Mish...
• Keywords: Proteostasis

Significance Disordered epithelial proteostasis is strongly implicated in the pathobiology of pulmonary fibrosis. We found that a small molecule specifically restores protein translation by EIF2B during activation integrated stress response, ISRIB, attenuated severity fibrosis young adult and old mice. Our data support multicellular model which relieving block to differentiation induced response slows recruitment profibrotic monocyte-derived alveolar macrophages attenuate A loss resilience aging would further slow repair, perhaps explaining increased risk elderly.