期刊
EUROPEAN RESPIRATORY JOURNAL
卷 42, 期 6, 页码 1633-1645出版社
EUROPEAN RESPIRATORY SOC JOURNALS LTD
DOI: 10.1183/09031936.00182412
关键词
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资金
- British Lung Foundation [F07/6]
- Medical Research Council [G0800340]
- CASE
- Wellcome Trust [084382/Z/07/Z]
- European Commission [HEALTH-F2- 2007-2224]
- European IPF Network
- Wellcome Trust [084382/Z/07/Z] Funding Source: Wellcome Trust
- MRC [G0800340] Funding Source: UKRI
- Medical Research Council [G0800340] Funding Source: researchfish
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 (BILE), and to evaluate a therapeutic dosing regimen for preclinical drug evaluation. A detailed characterisation of BILE was performed using standard end-point measures (lung hydroxyproline and histology). High resolution micro-CT (similar to 13.7 mu m 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-beta 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 BILE allows robust evaluation of therapeutic dosing once fibrosis is already well established, requiring fewer mice than conventional biochemical end-points.
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