Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis.

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.

• 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 McQuattie-Pimentel, Katherine A Gruner, Manu Jain, Jacob I Sznajder, Richard I Morimoto, Paul A Reyfman, Cara J Gottardi, G R Scott Budinger, Alexander V Misharin
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 20 (05 18 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 33972447 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• 2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide
• Acetamides
• Cyclohexylamines
• Bleomycin
• Asbestos

Topics

• Acetamides (pharmacology, therapeutic use)
• Age Factors
• Alveolar Epithelial Cells (cytology, drug effects)
• Animals
• Asbestos
• Bleomycin
• Cell Differentiation (drug effects)
• Cell Movement (drug effects)
• Cyclohexylamines (pharmacology, therapeutic use)
• Macrophages, Alveolar (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Proteostasis (drug effects, physiology)
• Pulmonary Fibrosis (chemically induced, drug therapy, pathology)
• Stress, Physiological (drug effects)