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Ex vivo micro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation

Chris J. Scotton, Brian Hayes, Robert Alexander, Arnab Datta, Ellen J. Forty, Paul F. Mercer, Andy Blanchard, Rachel C. Chambers
European Respiratory Journal 2013 42: 1633-1645; DOI: 10.1183/09031936.00182412
Chris J. Scotton
1Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London
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  • For correspondence: c.scotton@ucl.ac.uk
Brian Hayes
2Fibrosis DPU, GlaxoSmithKline, Stevenage, UK
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Robert Alexander
1Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London
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Arnab Datta
1Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London
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Ellen J. Forty
1Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London
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Paul F. Mercer
1Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London
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Andy Blanchard
2Fibrosis DPU, GlaxoSmithKline, Stevenage, UK
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Rachel C. Chambers
1Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London
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Abstract

Research into the pathogenesis underlying the development of idiopathic pulmonary fibrosis is hampered by a repertoire of animal models that fail to recapitulate all the features of the human disease. Better use and understanding of what the animal models represent may improve clinical predictability. We interrogated ex vivo micro-computed tomography (CT) as a novel end-point measure in the mouse model of bleomycin-induced lung fibrosis (BILF), and to evaluate a therapeutic dosing regimen for preclinical drug evaluation.

A detailed characterisation of BILF was performed using standard end-point measures (lung hydroxyproline and histology). High resolution micro-CT (∼13.7 μm voxel size) was evaluated for quantifying the extent and severity of lung fibrosis.

The period from 14 to 28 days following bleomycin instillation represents progression of established fibrosis. A therapeutic dosing regimen during this period was validated using a transforming growth factor-β receptor-1 kinase inhibitor, and micro-CT provided a highly sensitive and quantitative measure of fibrosis. Moreover, fibrotic lesions did not completely resolve, but instead persisted for ≥6 months following a single insult with bleomycin.

Ex vivo micro-CT analysis of BILF allows robust evaluation of therapeutic dosing once fibrosis is already well established, requiring fewer mice than conventional biochemical end-points.

Abstract

Micro-CT has improved out understanding of the bleomycin model of fibrotic lung disease for preclinical drug evaluation http://ow.ly/p73De

Footnotes

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

  • Support statement: The authors are grateful to the following grant agencies for funding: British Lung Foundation (C.J. Scotton Research Fellowship F07/6); Medical Research Council (C.J. Scotton Career Development Award G0800340; R.C. Chambers CASE Award 2009–2012); Wellcome Trust (A. Datta Clinical Research Training Fellowship 084382/Z/07/Z); European Commission (R.C. Chambers Framework 7 Programme HEALTH-F2- 2007-2224); and the European IPF Network). SB525334A was donated by GlaxoSmithKline (Stevenage, UK).

  • Conflict of interest: Disclosures can be found alongside the online version of this article at www.erj.ersjournals.com

  • Received November 12, 2012.
  • Accepted February 4, 2013.
  • ©ERS 2013

ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 3.0.

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Ex vivo micro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation
Chris J. Scotton, Brian Hayes, Robert Alexander, Arnab Datta, Ellen J. Forty, Paul F. Mercer, Andy Blanchard, Rachel C. Chambers
European Respiratory Journal Dec 2013, 42 (6) 1633-1645; DOI: 10.1183/09031936.00182412

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Ex vivo micro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation
Chris J. Scotton, Brian Hayes, Robert Alexander, Arnab Datta, Ellen J. Forty, Paul F. Mercer, Andy Blanchard, Rachel C. Chambers
European Respiratory Journal Dec 2013, 42 (6) 1633-1645; DOI: 10.1183/09031936.00182412
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