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Exuberant fibroblast activity compromises lung function via ADAMTS4.
Nature. 2020 Nov; 587(7834):466-471.Nat

Abstract

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.

Authors+Show Affiliations

Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, MA, USA. Department of Anesthesia, Harvard Medical School, Boston, MA, USA.Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, TN, USA.State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, MA, USA. Department of Anesthesia, Harvard Medical School, Boston, MA, USA.Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, MA, USA.Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.Section of Critical Care Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.No affiliation info availableMatrix Biology Program, Benaroya Research Institute, Seattle, WA, USA.Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, USA. Pennington Biomedical Research Center, Baton Rouge, LA, USA.Department of Emergency Medicine and Medicine, Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.Department of Emergency Medicine and Medicine, Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.Department of Emergency Medicine of Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan. Clinical Informatics and Medical Statistics Research Center of Chang Gung University, Taoyuan, Taiwan.State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. paul.thomas@stjude.org.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33116313

Citation

Boyd, David F., et al. "Exuberant Fibroblast Activity Compromises Lung Function Via ADAMTS4." Nature, vol. 587, no. 7834, 2020, pp. 466-471.
Boyd DF, Allen EK, Randolph AG, et al. Exuberant fibroblast activity compromises lung function via ADAMTS4. Nature. 2020;587(7834):466-471.
Boyd, D. F., Allen, E. K., Randolph, A. G., Guo, X. J., Weng, Y., Sanders, C. J., Bajracharya, R., Lee, N. K., Guy, C. S., Vogel, P., Guan, W., Li, Y., Liu, X., Novak, T., Newhams, M. M., Fabrizio, T. P., Wohlgemuth, N., Mourani, P. M., Wight, T. N., ... Thomas, P. G. (2020). Exuberant fibroblast activity compromises lung function via ADAMTS4. Nature, 587(7834), 466-471. https://doi.org/10.1038/s41586-020-2877-5
Boyd DF, et al. Exuberant Fibroblast Activity Compromises Lung Function Via ADAMTS4. Nature. 2020;587(7834):466-471. PubMed PMID: 33116313.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exuberant fibroblast activity compromises lung function via ADAMTS4. AU - Boyd,David F, AU - Allen,E Kaitlynn, AU - Randolph,Adrienne G, AU - Guo,Xi-Zhi J, AU - Weng,Yunceng, AU - Sanders,Catherine J, AU - Bajracharya,Resha, AU - Lee,Natalie K, AU - Guy,Clifford S, AU - Vogel,Peter, AU - Guan,Wenda, AU - Li,Yimin, AU - Liu,Xiaoqing, AU - Novak,Tanya, AU - Newhams,Margaret M, AU - Fabrizio,Thomas P, AU - Wohlgemuth,Nicholas, AU - Mourani,Peter M, AU - ,, AU - Wight,Thomas N, AU - Schultz-Cherry,Stacey, AU - Cormier,Stephania A, AU - Shaw-Saliba,Kathryn, AU - Pekosz,Andrew, AU - Rothman,Richard E, AU - Chen,Kuan-Fu, AU - Yang,Zifeng, AU - Webby,Richard J, AU - Zhong,Nanshan, AU - Crawford,Jeremy Chase, AU - Thomas,Paul G, Y1 - 2020/10/28/ PY - 2019/07/16/received PY - 2020/07/30/accepted PY - 2020/10/30/pubmed PY - 2020/10/30/medline PY - 2020/10/29/entrez SP - 466 EP - 471 JF - Nature JO - Nature VL - 587 IS - 7834 N2 - Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/33116313/Exuberant_fibroblast_activity_compromises_lung_function_via_ADAMTS4 L2 - https://doi.org/10.1038/s41586-020-2877-5 DB - PRIME DP - Unbound Medicine ER -
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