Magnetic resonance imaging for noninvasive assessment of lung fibrosis onset and progression: cross-validation and comparison of different magnetic resonance imaging protocols with micro-computed tomography and histology in the bleomycin-induced mouse model.

Abstract

Bleomycin instillation is frequently used to model lung fibrosis, although the onset and severity of pathology varies highly between mice. This makes non-invasive fibrosis detection and quantification essential to obtain a comprehensive analysis of the disease course and to validate novel therapies. Magnetic resonance imaging (MRI) of lung disease progression and therapy may provide such a sensitive in vivo readout of lung fibrosis, bypassing radiotoxicity concerns (when using micro-CT [μCT]) and elaborate invasive end point measurements (histology). We aimed to optimize and evaluate 3 different lung MRI contrast and acquisition methods to visualize disease onset and progression in the bleomycin-induced mouse model of lung fibrosis using a small-animal MRI scanner. For validation, we compared the MRI results with established μCT and histological measures of lung fibrosis. Free-breathing bleomycin-instilled and control mice were scanned in vivo with respiration-triggered conventional, ultrashort echo time and self-gated MRI pulse sequences (9.4 T) and μCT at baseline and weekly at days 7, 14, 21, and 28 after bleomycin instillation. After the last imaging time point, the mice were killed and the lungs were isolated for criterion standard histological analysis of lung fibrosis and quantification of lung collagen content for validation of the imaging results. The agreement between quantitative MRI and μCT data and standard measurements was analyzed by linear regression. All 3 MRI protocols were able to visualize and quantify lung pathology onset and progression in individual bleomycin-instilled mice. In vivo MRI results were in excellent agreement with in vivo μCT and criterion standard histological measures of lung fibrosis. Ultrashort echo time MRI appeared particularly useful for detecting early disease; self-gated MRI, for improved breathing motion handling. Magnetic resonance imaging sensitively visualizes and quantifies lung fibrosis in vivo, which makes it a noninvasive, translatable, safe, and potentially more versatile alternative to invasive methods or μCT, thereby stimulating pathogenesis and preclinical research.