دورية أكاديمية
Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis.
| العنوان: | Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. |
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| المؤلفون: | Ng B; National Heart Centre Singapore, 169609 Singapore, Singapore.; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Dong J; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., D'Agostino G; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Viswanathan S; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Widjaja AA; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Lim WW; National Heart Centre Singapore, 169609 Singapore, Singapore.; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Ko NSJ; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Tan J; National Heart Centre Singapore, 169609 Singapore, Singapore.; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Chothani SP; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Huang B; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Xie C; National Heart Centre Singapore, 169609 Singapore, Singapore., Pua CJ; National Heart Centre Singapore, 169609 Singapore, Singapore., Chacko AM; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Guimarães-Camboa N; Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt 60590, Germany.; German Center for Cardiovascular Research DZHK, Berlin 10785, Germany.; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA., Evans SM; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA., Byrne AJ; Fibrosis Research Group, Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK., Maher TM; Fibrosis Research Group, Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK.; NIHR Biomedical Research Unit, Royal Brompton Hospital, London SW7 2AZ, UK., Liang J; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.; Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Jiang D; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.; Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Noble PW; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.; Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Schafer S; National Heart Centre Singapore, 169609 Singapore, Singapore.; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore., Cook SA; National Heart Centre Singapore, 169609 Singapore, Singapore. stuart.cook@duke-nus.edu.sg.; Duke-National University of Singapore Medical School, 169857 Singapore, Singapore.; National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.; MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK. |
| المصدر: | Science translational medicine [Sci Transl Med] 2019 Sep 25; Vol. 11 (511). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Association for the Advancement of Science |
| مواضيع طبية MeSH: | Idiopathic Pulmonary Fibrosis/*drug therapy , Interleukin-11/*therapeutic use, Animals ; Antibodies, Neutralizing/pharmacology ; Antibodies, Neutralizing/therapeutic use ; Bleomycin ; Fibroblasts/pathology ; Humans ; Idiopathic Pulmonary Fibrosis/pathology ; Interleukin-11 Receptor alpha Subunit/metabolism ; Lung/pathology ; Mice, Knockout ; Severity of Illness Index ; Signal Transduction ; Up-Regulation |
| مستخلص: | Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here, we show that interleukin-11 ( IL11 ) is up-regulated in the lung of patients with IPF, associated with disease severity, and IL-11 is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2 + ), collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent, posttranscriptional manner. In mice, fibroblast-specific transgenic expression or administration of murine IL-11 induces lung myofibroblasts and causes lung fibrosis. IL-11 receptor subunit alpha-1 ( Il11ra1 )-deleted mice, whose lung fibroblasts are unresponsive to profibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11-neutralizing antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK and SMAD activation in mice. These data prioritize IL-11 as a drug target for lung fibrosis and IPF. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.) |
| معلومات مُعتمدة: | CS-2013-13-017 United Kingdom DH_ Department of Health; MC_U120085815 United Kingdom MRC_ Medical Research Council |
| المشرفين على المادة: | 0 (Antibodies, Neutralizing) 0 (Il11ra1 protein, mouse) 0 (Interleukin-11) 0 (Interleukin-11 Receptor alpha Subunit) 11056-06-7 (Bleomycin) |
| تواريخ الأحداث: | Date Created: 20190927 Date Completed: 20200820 Latest Revision: 20210110 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1126/scitranslmed.aaw1237 |
| PMID: | 31554736 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1946-6242 |
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| DOI: | 10.1126/scitranslmed.aaw1237 |