Imaging Biomarkers and Pathobiological Profiling in a Rat Model of Drug-Induced Interstitial Lung Disease Induced by Bleomycin

Abstract

A large number of systemically administered drugs have the potential to cause drug-induced interstitial lung disease (DIILD). We aim to characterize a model of DIILD in the rat and develop imaging biomarkers (IBs) for detection and quantification of DIILD. In this study, Sprague-Dawley rats received one single dose of intratracheal (i.t.) bleomycin and were longitudinally imaged at day 0, 3, 7, 14, 21, and 28 post dosing, applying the imaging techniques magnetic resonance imaging (MRI) and positron emission tomography (PET)/computed tomography (CT). Bronchoalveolar lavage fluid (BALF) was analyzed for total protein and inflammatory cells. Lungs were saved for further evaluation by gene analysis using quantitative-PCR and by histology. Lung sections were stained with Masson's-Trichrome staining and evaluated by modified Ashcroft score. Gene expression profiling of inflammatory and fibrotic markers was performed on lung tissue homogenates. Bleomycin induced significant increase in total protein concentration and total cell count in bronchoalveolar lavage (BAL), peaking at day 3 (p > 0.001) and day 7 (p > 0.001) compared to control, respectively. Lesions measured by MRI and PET signal in the lungs of bleomycin challenged rats were significantly increased during days 3-14, peaking at day 7. Two subgroups of animals were identified as low- and high-responders by their different change in total lung volume. Both groups showed signs of inflammation initially, while at later time points, the low-responder group recovered toward control, and the high-responder group showed sustained lung volume increase, and significant increase of lesion volume (p < 0.001) compared to control. Lastly, important inflammatory and pro-fibrotic markers were assessed from lung tissue, linking observed imaging pathological changes to gene expression patterns. In conclusion, bleomycin-induced lung injury is an adequate animal model for DIILD studies and for translational lung injury assessment by MRI and PET imaging. The scenario comprised disease responses, with different fractions of inflammation and fibrosis. Thereby, this study improved the understanding of imaging and biological biomarkers in DIILD and lung injury.

Keywords: animal model; bleomycin; drug-induced interstitial lung disease; imaging; inflammation; lung injury; magnetic resonance imaging; positron emission tomography.