Exuberant fibroblast activity compromises lung function via ADAMTS4

David F. Boyd, E. Kaitlynn Allen, Adrienne G. Randolph, Xi-zhi J. Guo, Yunceng Weng, Catherine J. Sanders, Resha Bajracharya, Natalie K. Lee, Clifford S. Guy, Peter Vogel, Wenda Guan, Yimin Li, Xiaoqing Liu, Tanya Novak, Margaret M. Newhams, Thomas P. Fabrizio, Nicholas Wohlgemuth, Peter M. Mourani, Thomas N. Wight, Stacey Schultz-Cherry, Stephania A. Cormier, Kathryn Shaw-Saliba, Andrew Pekosz, Richard E. Rothman, Kuan-Fu Chen, Zifeng Yang, Richard J. Webby, Nanshan Zhong, Jeremy Chase Crawford and Paul G. Thomas ()
Additional contact information
David F. Boyd: St Jude Children’s Research Hospital
E. Kaitlynn Allen: St Jude Children’s Research Hospital
Adrienne G. Randolph: Critical Care and Pain Medicine
Xi-zhi J. Guo: St Jude Children’s Research Hospital
Yunceng Weng: National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University
Catherine J. Sanders: St Jude Children’s Research Hospital
Resha Bajracharya: St Jude Children’s Research Hospital
Natalie K. Lee: St Jude Children’s Research Hospital
Clifford S. Guy: St Jude Children’s Research Hospital
Peter Vogel: St Jude Children’s Research Hospital
Wenda Guan: National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University
Yimin Li: National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University
Xiaoqing Liu: National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University
Tanya Novak: Critical Care and Pain Medicine
Margaret M. Newhams: Critical Care and Pain Medicine
Thomas P. Fabrizio: St Jude Children’s Research Hospital
Nicholas Wohlgemuth: St Jude Children’s Research Hospital
Peter M. Mourani: University of Colorado School of Medicine and Children’s Hospital Colorado
Thomas N. Wight: Benaroya Research Institute
Stacey Schultz-Cherry: St Jude Children’s Research Hospital
Stephania A. Cormier: Louisiana State University
Kathryn Shaw-Saliba: Johns Hopkins University School of Medicine
Andrew Pekosz: Johns Hopkins Bloomberg School of Public Health
Richard E. Rothman: Johns Hopkins University School of Medicine
Kuan-Fu Chen: Department of Emergency Medicine of Chang Gung Memorial Hospital at Keelung
Zifeng Yang: National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University
Richard J. Webby: St Jude Children’s Research Hospital
Nanshan Zhong: National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University
Jeremy Chase Crawford: St Jude Children’s Research Hospital
Paul G. Thomas: St Jude Children’s Research Hospital

Nature, 2020, vol. 587, issue 7834, 466-471

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2877-5

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