Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis

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