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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

BMC Pulmonary Medicine 1/2015

Structural and functional correlations in a large animal model of bleomycin-induced pulmonary fibrosis

BMC Pulmonary Medicine > Ausgabe 1/2015
Louise Organ, Barbara Bacci, Emmanuel Koumoundouros, Garry Barcham, Marjorie Milne, Wayne Kimpton, Chrishan Samuel, Ken Snibson
Wichtige Hinweise

Competing interests

The authors declare that they have no competing interest.

Authors’ contributions

LO was the principal researcher for the study, and designed the study together with KS. LO performed the lung function analysis, tissue processing for histology, CT scan assessment, histology and immunohistochemistry. LO performed histopathology assessment with BB’s assistance, Masson trichrome staining and collagen analysis, immunohistochemistry, BAL sampling and cell counts. LO also performed the statistical analysis and drafted the manuscript. BB provided assistance with developing the scoring system for assessing the histopathology and subsequent scoring of the tissue and analysis of histopathology. MM performed the CT scan EK designed the software program to assess the lung function and assisted in the lung function analysis. CS assisted with the hydroxyproline assay and assessment GB assisted in the sheep trial with animal handling and tissue processing at autopsy. WK assisted in the design of the study and helped draft the manuscript. KS assisted with LO to develop the study, and assisted in its design and coordination. KS also performed the bronchoscopy technique for lung function and helped to draft the manuscript. All authors read and approved the final manuscript.



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.


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.


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.


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.
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