title: Structural and functional correlations in a large animal model of bleomycin-induced pulmonary fibrosis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a severe and progressive respiratory disease with poor prognosis. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Pre-clinical animal models are currently largely limited to small animals which have a number of shortcomings. We have previously shown that fibrosis is induced in isolated sheep lung segments 14 days after bleomycin treatment. This study aimed to determine whether bleomycin-induced fibrosis and associated functional changes persisted over a seven-week period.
  
  
  METHODS
  Two separate lung segments in nine sheep received two challenges two weeks apart of either, 3U bleomycin (BLM), or saline (control). Lung function in these segments was assessed by a wedged-bronchoscope procedure after bleomycin treatment. Lung tissue, and an ex vivo CT analysis were used to assess for the persistence of inflammation, fibrosis and collagen content in this model.
  
  
  RESULTS
  Fibrotic changes persisted up to seven weeks in bleomycin-treated isolated lung segments (Pathology scores: bleomycin12.27 ± 0.07 vs. saline 4.90 ± 1.18, n = 9, p = 0.0003). Localization of bleomycin-induced injury and increased tissue density was confirmed by CT analysis (mean densitometric CT value: bleomycin -698 ± 2.95 Hounsfield units vs. saline -898 ± 2.5 Hounsfield units, p = 0.02). Masson's trichrome staining revealed increased connective tissue in bleomycin segments, compared to controls (% blue staining/total field area: 8.5 ± 0.8 vs. 2.1 ± 0.2 %, n = 9, p < 0.0001). bleomycin-treated segments were significantly less compliant from baseline at 7 weeks post treatment compared to control-treated segments (2.05 ± 0.88 vs. 4.97 ± 0.79 mL/cmH20, n = 9, p = 0.002). There was also a direct negative correlation between pathology scores and segmental compliance.
  
  
  CONCLUSIONS
  We show that there is a correlation between fibrosis and correspondingly poor lung function which persist for up to seven weeks after bleomycin treatment in this large animal model of pulmonary fibrosis.
authors.affiliation: Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, VIC, Australia. lorgan@student.unimelb.edu.au.
authors.forename: Louise
authors.initials: L
authors.lastname: Organ
authors.affiliation: Faculty of Veterinary and Agricultural Science, The University of Melbourne, Werribee, VIC, Australia. bbacci@unimelb.edu.au.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bacci
authors.affiliation: Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, VIC, Australia. emmanuel@unimelb.edu.au.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Koumoundouros
authors.affiliation: Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, VIC, Australia. garryjb@unimelb.edu.au.
authors.forename: Garry
authors.initials: G
authors.lastname: Barcham
authors.affiliation: Faculty of Veterinary and Agricultural Science, The University of Melbourne, Werribee, VIC, Australia. mmil@unimelb.edu.au.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Milne
authors.affiliation: Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, VIC, Australia. w.kimpton@unimelb.edu.au.
authors.forename: Wayne
authors.initials: W
authors.lastname: Kimpton
authors.affiliation: Department of Pharmacology, Monash University, Clayton, VIC, Australia. chrishan.samuel@monash.edu.
authors.forename: Chrishan
authors.initials: C
authors.lastname: Samuel
authors.affiliation: Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, VIC, Australia. ksnibson@unimelb.edu.au.
authors.forename: Ken
authors.initials: K
authors.lastname: Snibson
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001761:Bleomycin / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000175:diagnosis* / Q000503:physiopathology; D012756:Sheep; D014057:Tomography, X-Ray Computed
chemical_list: D001761:Bleomycin; D003094:Collagen