Title

Exuberant fibroblast activity compromises lung function via ADAMTS4

Authors

David F. Boyd, St. Jude Children's Research Hospital
E. Kaitlynn Allen, St. Jude Children's Research Hospital
Adrienne G. Randolph, Children's Hospital Boston
Xi zhi J. Guo, St. Jude Children's Research Hospital
Yunceng Weng, 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, Guangzhou Medical University
Yimin Li, Guangzhou Medical University
Xiaoqing Liu, Guangzhou Medical University
Tanya Novak, Children's Hospital Boston
Margaret M. Newhams, Children's Hospital Boston
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
Michele Kong, Children's of Alabama
Ronald C. Sanders, Arkansas Children's Hospital
Katherine Irby, Arkansas Children's Hospital
Katri Typpo, Diamond Children's Medical Center
Barry Markovitz, Children's Hospital Los Angeles
Natalie Cvijanovich, UCSF Benioff Children's Hospital Oakland
Heidi Flori, UCSF Benioff Children's Hospital Oakland
Adam Schwarz, CHOC Children‘s UC Irvine School of Medicine
Nick Anas, CHOC Children‘s UC Irvine School of Medicine
Peter Mourani, Children’s Hospital Colorado
Angela Czaja, Children’s Hospital Colorado
Gwenn McLaughlin, Holtz Children's Hospital
Matthew Paden, Children’s Healthcare of Atlanta
Keiko Tarquinio, Children’s Healthcare of Atlanta
Bria M. Coates, Ann & Robert H. Lurie Children's Hospital of Chicago
Neethi Pinto, University of Chicago Medicine Comer Children's Hospital

Document Type

Article

Publication Date

11-19-2020

Abstract

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. 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.

Publication Source (Journal or Book title)

Nature

First Page

466

Last Page

471

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