title: Ex vivo micro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation.
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.
authors.affiliation: UCL Respiratory, University College London, London.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Scotton
authors.forename: Brian
authors.initials: B
authors.lastname: Hayes
authors.forename: Robert
authors.initials: R
authors.lastname: Alexander
authors.forename: Arnab
authors.initials: A
authors.lastname: Datta
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Forty
authors.forename: Paul F
authors.initials: PF
authors.lastname: Mercer
authors.forename: Andy
authors.initials: A
authors.lastname: Blanchard
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000032:analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011658:Pulmonary Fibrosis / Q000139:chemically induced*; D011810:Quinoxalines / Q000737:chemistry; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D055114:X-Ray Microtomography / Q000379:methods*
chemical_list: C521813:6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline; D007093:Imidazoles; D011810:Quinoxalines; D018125:Receptors, Transforming Growth Factor beta; D001761:Bleomycin; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I