ArticleProceedings of the National Academy of Sciences of the United States of America2021
Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis.
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Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 1 of them a synthesis that pooled it.
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65citing papers in PubMed, 1 pooled it
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Who cites it
65 citing papers in PubMed, 1 synthesis or guideline pooled it, 91 citations in OpenAlex.
- Shared and niche-specific transcriptional signatures of macrophage aging revealed by a cross-tissue meta-analysis.BMC biology · 2026Pooled it
- VEGFA-Positive Macrophages Regulate Aqueous Humor Outflow in Aged Mice and Humans.bioRxiv : the preprint server for biology · 2026Article
- Murine models of pulmonary fibrosis: mechanisms, limitations and translational insights.European respiratory review : an official journal of the European Respiratory Society · 2026Review
- Endoplasmic reticulum stress and the unfolded protein response in lung diseases: molecular pathways and therapeutic interventions.The Journal of pathology · 2026Review
- Hallmarks of the ageing lung: 10 years later.The European respiratory journal · 2026Review
- Progenitor Resilience and the Early Onset of Chronic Lung Diseases: NHLBI workshop report.American journal of respiratory cell and molecular biology · 2026Article
- Unlocking Alveolar Regeneration: AT2 Stem Cells, Signaling Networks, and Therapeutic Frontiers.Stem cell reviews and reports · 2026Review
- Advances in understanding mitophagy's role in lung injury.Chinese journal of traumatology = Zhonghua chuang shang za zhi · 2026Review
- Role of Activating Transcription Factor 4 in Metabolic, Neurologic, and Ocular Diseases.Cells · 2026Review
- The Janus framework of the integrated stress response: from homeostasis to maladaptation.Life science alliance · 2026Review
- Transcriptomic signature-guided depletion of intermediate alveolar epithelial cells ameliorates pulmonary fibrosis in mice.Nature communications · 2026Article
- The effect and mechanism of total alkaloids ofFrontiers in pharmacology · 2026Article
- Integrated Stress Response and Necroptosis Drive Epithelial Dysfunction in Crohn's Disease: Repurposing Cancer Drugs for Permeability Barrier Healing.Gastro hep advances · 2026Article
- Dihydroquercetin Attenuates Silica-Induced Pulmonary Fibrosis by Modulating the Gut Microbiota and the Serum Metabolites in Mice.Food science & nutrition · 2026Article
- Review
- Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice.The Journal of clinical investigation · 2025Article
- Stress, plasticity, and fibrosis: unfolding the role of the IRE1α/RIDD/Fgfr2 axis.The Journal of clinical investigation · 2025Article
- Profibrotic monocyte-derived alveolar macrophages as a biomarker and therapeutic target in systemic sclerosis-associated interstitial lung disease.bioRxiv : the preprint server for biology · 2025Article
- Phenotypic pharmacology of novel Complex I inhibitors eliciting tissue repair concurrent to control of inflammation.The Journal of pharmacology and experimental therapeutics · 2025Article
- Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.JCI insight · 2025Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 2 institutions in 2 countries.
Satoshi WatanabeDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0002-2579-8472
Nikolay S MarkovDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0002-3659-4387
Ziyan LuDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Raul Piseaux AillonDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Saul SoberanesDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0002-6820-9711
Constance E RunyanDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Ziyou RenDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Rogan A GrantDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0003-0655-0882
Mariana MacielDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0002-1791-818X
Hiam Abdala-ValenciaDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Yuliya PolitanskaDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Kiwon NamDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Lango SichizyaDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Hermon G KihshenDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Nikita JoshiDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0001-8330-0663
Alexandra C McQuattie-PimentelDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Katherine A GrunerMouse Histology and Phenotyping Laboratory, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611.
Manu JainDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Jacob I SznajderDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Richard I MorimotoDepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208.ORCID 0000-0002-3431-445X
Paul A ReyfmanDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0002-6435-6001
Cara J GottardiDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0003-0912-7617
G R Scott BudingerDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; s-buding@northwestern.edu a-misharin@northwestern.edu.ORCID 0000-0002-3114-5208
Alexander V MisharinDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; s-buding@northwestern.edu a-misharin@northwestern.edu.ORCID 0000-0003-2879-3789
Northwestern University · USKanazawa University · JP
Funding
Tumor Environment and Metastasis (TEAM) Research ProgramP30CA060553 · NCI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI LEONIDAS C. PLATANIAS · 1993 to 2026
$153.9MRole of LUBAC and Na K-ATPase in Acute Lung InjuryP01HL071643 · NHLBI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI SZNAJDER, JACOB I · 2003 to 2019
$30.8MTissue resident macrophages regulate proteostasis in the aging lungP01AG049665 · NIA · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Benjamin David Singer · 2015 to 2026
$26.9MTechnology CoreU19AI135964 · NIAID · NORTHWESTERN UNIVERSITY AT CHICAGO · PI LUIS A. Nunes AMARAL · 2018 to 2026
$24.7MPREDOCTORAL AND POSTDOCTORAL TRAINING PROGRAM IN AGING AND DEMENTIAT32AG020506 · NIA · NORTHWESTERN UNIVERSITY AT CHICAGO · PI ROBERT J VASSAR, SANDRA WEINTRAUB · 2002 to 2026
$9.9MTraining Program In Lung SciencesT32HL076139 · NHLBI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI KAREN M RIDGE, Jacob I Sznajder · 2004 to 2026
$9.6MC. elegans Model for Neurodegenerative Diseases of AgingR37AG026647 · NIA · NORTHWESTERN UNIVERSITY · PI MORIMOTO, RICHARD I · 2010 to 2019
$3.9MSignaling in the lung induced by particulate matter air pollutionR01ES013995 · NIEHS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI BUDINGER, GR SCOTT · 2006 to 2015
$3.3MRegulation of Peripheral ProteostasisRF1AG057296 · NIA · NORTHWESTERN UNIVERSITY · PI MORIMOTO, RICHARD I · 2017 to 2017
$3.0MLung transplant injury drives chronic lung allograft dysfunction via recruitment ofmonocyte-derived alveolar macrophagesR01HL153312 · NHLBI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI MISHARIN, ALEXANDER · 2020 to 2023
$2.9MWnt-beta-catenin cross interactions in alveolar macrophages and epithelial cells in persistence of SSc-ILDR01HL134800 · NHLBI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI GOTTARDI, CARA J · 2018 to 2021
$2.9MCadherin-catenin regulation in dividing epithelial cellsR01GM129312 · NIGMS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI GOTTARDI, CARA J · 2018 to 2021
$1.5MBLRD VA I01 BX000201NCI NIH HHS P30 CA060553NHLBI NIH HHS F32 HL136111NHLBI NIH HHS K08 HL146943NHLBI NIH HHS P01 HL071643NHLBI NIH HHS R01 HL134800NHLBI NIH HHS R01 HL153312NHLBI NIH HHS R56 HL135124NHLBI NIH HHS T32 HL076139NIAID NIH HHS U19 AI135964NIA NIH HHS F31 AG071225NIA NIH HHS P01 AG049665NIA NIH HHS R37 AG026647NIA NIH HHS RF1 AG057296NIA NIH HHS T32 AG020506NIEHS NIH HHS R01 ES013995NIGMS NIH HHS R01 GM129312NIH HHS S10 OD010398
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.
Indexed as
AcetamidesAge FactorsAlveolar Epithelial CellsAnimalsAsbestosBleomycinCell DifferentiationCell MovementCyclohexylaminesMacrophages, AlveolarMiceMice, Inbred C57BLProteostasisPulmonary FibrosisStress, Physiological2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamideAcetamidesAsbestosBleomycinCyclohexylaminesfibrosisISRIBproteostasis
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