Abstract
BackgroundIdiopathic 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.MethodsTwo 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.ResultsFibrotic 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.ConclusionsWe 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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a severe and progressive respiratory disease with poor prognosis
Isolation of fibrosis to bleomycin-treated lung region To confirm that the fibrosis induced by the segmental administration of bleomycin was localized to the treated lobes, an ex-vivo CT scan was performed on lungs removed at autopsy (Fig. 2)
Decreased lung compliance persists in bleomycin-treated segments Temporal changes in lung function in the individually treated segments were assessed in all sheep by measuring lung function before bleomycin or saline treatment, and again at 2, 4 and 7 weeks post –treatment
Summary
Idiopathic pulmonary fibrosis (IPF) is a severe and progressive respiratory disease with poor prognosis. The uncertainty about the duration and persistence of fibrosis in some bleomcyin rodent models has led some researchers to cast doubt over the appropriateness of using this model to trial novel therapies, one of the primary uses of the model [9]. For this reason, it is critical to determine whether a measurable fibrotic response is maintained for a sufficient period of time to trial novel therapies during the fibrotic phase in any animal model being considered for such experiments
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