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The importance of interventional timing in the bleomycin model of pulmonary fibrosis

Philipp Kolb, Chandak Upagupta, Megan Vierhout, Ehab Ayaub, Pierre Simon Bellaye, Jack Gauldie, Chiko Shimbori, Mark Inman, Kjetil Ask, Martin R.J. Kolb
European Respiratory Journal 2020 55: 1901105; DOI: 10.1183/13993003.01105-2019
Philipp Kolb
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
2These authors contributed equally to this work
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Chandak Upagupta
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
2These authors contributed equally to this work
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Megan Vierhout
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
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Ehab Ayaub
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
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Pierre Simon Bellaye
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
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Jack Gauldie
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
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Chiko Shimbori
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
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Mark Inman
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
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Kjetil Ask
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
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Martin R.J. Kolb
1Firestone Institute for Respiratory Health, Depts of Medicine, McMaster University, Hamilton, ON, Canada
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  • ORCID record for Martin R.J. Kolb
  • For correspondence: kolbm@mcmaster.ca
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5–7 days. This initial inflammation makes therapeutic timing crucial. To accurately assess antifibrotic efficacy, the intervention should inhibit fibrosis without impacting early inflammation.

Studies published between 2008 and 2019 using the bleomycin model to investigate pulmonary fibrosis were retrieved from PubMed, and study characteristics were analysed. Intervention-based studies were classified as either preventative (starting <7 days after bleomycin installation) or therapeutic (>7 days). In addition, studies were cross-referenced with current major clinical trials to assess the availability of preclinical rationale.

A total of 976 publications were evaluated. 726 investigated potential therapies, of which 443 (61.0%) were solely preventative, 166 (22.9%) were solely therapeutic and 105 (14.5%) were both. Of the 443 preventative studies, only 70 (15.8%) characterised inflammation during the model's early inflammatory phase. In the reported 145 IPF clinical trials investigating 93 compounds/combinations, only 25 (26.9%) interventions had any preclinical data on bleomycin available on PubMed.

Since 2008, we observed a shift (from <5% to 37.4%) in the number of studies evaluating drugs in the therapeutic setting in the bleomycin model. While this shift is encouraging, further characterisation of early inflammation and appropriate preclinical therapeutic testing are still needed. This will facilitate fruitful drug development in IPF, and more therapeutic strategies for patients with this devastating disease.

Abstract

Preclinical models are important to decipher mechanisms of disease, identify novel treatment targets and develop new drugs. The bleomycin model is the standard model for pulmonary fibrosis, but it is often used incorrectly, as shown by this meta-analysis. http://bit.ly/39qboxP

Footnotes

  • This article has an editorial commentary: https://doi.org/10.1183/13993003.00811-2020

  • This article has supplementary material available from erj.ersjournals.com

  • Conflict of interest: P. Kolb has nothing to disclose.

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

  • Conflict of interest: M. Vierhout has nothing to disclose.

  • Conflict of interest: E. Ayaub has nothing to disclose.

  • Conflict of interest: P.S. Bellaye has nothing to disclose.

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

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

  • Conflict of interest: M. Inman has nothing to disclose.

  • Conflict of interest: K. Ask reports grants from Boehringer Ingelheim, GSK, Prometic, Alkermes, Pharmaxis, Respivert, Indalo, Canadian Institutes for Health Research, Kniksa, Avalyn, National Sciences and Engineering Research Council, Ontario Thoracic Society, Canadian Pulmonary Fibrosis Foundation, Actelion, Gilead, Patara, Synairgen and Unity, outside the submitted work.

  • Conflict of interest: M.R.J. Kolb reports grants and personal fees from Roche, Boehringer Ingelheim and Prometic, grants from GSK, Respivert, Alkermes, Pharmaxis and Canadian Institute for Health Research, personal fees from Genoa Indalo, Third Pole and Pieris, outside the submitted work

  • Support statement: This work was supported by the Institute of Circulatory and Respiratory Health. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received June 5, 2019.
  • Accepted February 24, 2020.
  • Copyright ©ERS 2020
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The importance of interventional timing in the bleomycin model of pulmonary fibrosis
Philipp Kolb, Chandak Upagupta, Megan Vierhout, Ehab Ayaub, Pierre Simon Bellaye, Jack Gauldie, Chiko Shimbori, Mark Inman, Kjetil Ask, Martin R.J. Kolb
European Respiratory Journal Jun 2020, 55 (6) 1901105; DOI: 10.1183/13993003.01105-2019

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The importance of interventional timing in the bleomycin model of pulmonary fibrosis
Philipp Kolb, Chandak Upagupta, Megan Vierhout, Ehab Ayaub, Pierre Simon Bellaye, Jack Gauldie, Chiko Shimbori, Mark Inman, Kjetil Ask, Martin R.J. Kolb
European Respiratory Journal Jun 2020, 55 (6) 1901105; DOI: 10.1183/13993003.01105-2019
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