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The self-fulfilling prophecy of pulmonary fibrosis: a selective inspection of pathological signalling loops

Ashley R. Rackow, David J. Nagel, Claire McCarthy, Jennifer Judge, Shannon Lacy, Margaret A.T. Freeberg, Thomas H. Thatcher, R. Matthew Kottmann, Patricia J. Sime
European Respiratory Journal 2020 56: 2000075; DOI: 10.1183/13993003.00075-2020
Ashley R. Rackow
1Dept of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA
7Authors contributed equally to this work
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  • ORCID record for Ashley R. Rackow
David J. Nagel
2Division of Pulmonary Diseases and Critical Care, University of Rochester Medical Center, Rochester, NY, USA
7Authors contributed equally to this work
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Claire McCarthy
3National Cancer Institute, Bethesda, MD, USA
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Jennifer Judge
4Cook MyoSite, Pittsburgh, PA, USA
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Shannon Lacy
5US Army of Veterinary Corps, Fort Campbell, KY, USA
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Margaret A.T. Freeberg
6Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA
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Thomas H. Thatcher
6Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA
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R. Matthew Kottmann
2Division of Pulmonary Diseases and Critical Care, University of Rochester Medical Center, Rochester, NY, USA
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Patricia J. Sime
2Division of Pulmonary Diseases and Critical Care, University of Rochester Medical Center, Rochester, NY, USA
6Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA
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Abstract

Pulmonary fibrosis is a devastating, progressive disease and carries a prognosis worse than most cancers. Despite ongoing research, the mechanisms that underlie disease pathogenesis remain only partially understood. However, the self-perpetuating nature of pulmonary fibrosis has led several researchers to propose the existence of pathological signalling loops. According to this hypothesis, the normal wound-healing process becomes corrupted and results in the progressive accumulation of scar tissue in the lung. In addition, several negative regulators of pulmonary fibrosis are downregulated and, therefore, are no longer capable of inhibiting these feed-forward loops. The combination of pathological signalling loops and loss of a checks and balances system ultimately culminates in a process of unregulated scar formation. This review details specific signalling pathways demonstrated to play a role in the pathogenesis of pulmonary fibrosis. The evidence of detrimental signalling loops is elucidated with regard to epithelial cell injury, cellular senescence and the activation of developmental and ageing pathways. We demonstrate where these loops intersect each other, as well as common mediators that may drive these responses and how the loss of pro-resolving mediators may contribute to the propagation of disease. By focusing on the overlapping signalling mediators among the many pro-fibrotic pathways, it is our hope that the pulmonary fibrosis community will be better equipped to design future trials that incorporate the redundant nature of these pathways as we move towards finding a cure for this unrelenting disease.

Abstract

There are several signalling cascades involved in the progression of pulmonary fibrosis. Studying the complexity of these loops allows an examination of the ways in which fibrosis begets more fibrosis. https://bit.ly/3fcGifR

Footnotes

  • Conflict of interest: A.R. Rackow has nothing to disclose.

  • Conflict of interest: D.J. Nagel reports grants from National Heart, Lung, and Blood Institution (NIH T32 training grant), during the conduct of the study.

  • Conflict of interest: C. McCarthy has nothing to disclose.

  • Conflict of interest: J. Judge has nothing to disclose.

  • Conflict of interest: S. Lacy is employed by the US Army; the views expressed herein are those of the author and do not reflect the official policy or position of the Department of the Army, Department of Defense or the US Government.

  • Conflict of interest: M.A.T. Freeberg has nothing to disclose.

  • Conflict of interest: T.H. Thatcher reports grants from NIH, during the conduct of the study.

  • Conflict of interest: R.M. Kottmann reports grants from NIH, during the conduct of the study; and has a patent for LDH inhibitors as treatment for fibrosis and fibrotic-related disorders issued.

  • Conflict of interest: P.J. Sime reports grants from NIH, during the conduct of the study; grants from NIH, grants and personal fees for consultancy from UCB, personal fees for consultancy from Boehringer Ingelheim, personal fees from GSK, personal fees for data monitoring committee work from Intermune/Roche, personal fees for advisory board work from Prometic and Galecto, and funds for research from Guy Solimano and Greg Chandler Fund, outside the submitted work; and has a patent for methods of diagnosing and treating fibrosis issued, a patent for LDH inhibitors as treatment for fibrosis and fibrotic-related disorders issued, and a patent for method and apparatus to diagnose metastatic and progressive potential of cancer, fibrosis and other diseases pending.

  • Support statement: This work was supported by Boehringer Ingelheim and the National Heart, Lung, and Blood Institute (grants R01HL12090804, R01HL12700104 and T32HL066988).

  • Received January 13, 2020.
  • Accepted July 1, 2020.
  • Copyright ©ERS 2020
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The self-fulfilling prophecy of pulmonary fibrosis: a selective inspection of pathological signalling loops
Ashley R. Rackow, David J. Nagel, Claire McCarthy, Jennifer Judge, Shannon Lacy, Margaret A.T. Freeberg, Thomas H. Thatcher, R. Matthew Kottmann, Patricia J. Sime
European Respiratory Journal Nov 2020, 56 (5) 2000075; DOI: 10.1183/13993003.00075-2020

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The self-fulfilling prophecy of pulmonary fibrosis: a selective inspection of pathological signalling loops
Ashley R. Rackow, David J. Nagel, Claire McCarthy, Jennifer Judge, Shannon Lacy, Margaret A.T. Freeberg, Thomas H. Thatcher, R. Matthew Kottmann, Patricia J. Sime
European Respiratory Journal Nov 2020, 56 (5) 2000075; DOI: 10.1183/13993003.00075-2020
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    • Epithelial cell damage, reactive oxygen species and senescence generate a pathological signalling loop
    • Fibrotic pathogenic cascades from the activation of developmental and ageing pathways
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