Longitudinal micro-CT of preclinical models of lung disease provides biomarkers of disease and therapy that reveal compensatory changes in lung volume

Abstract

Because it provides information on dynamic disease processes, in vivo micro-CT is increasingly embraced in lung research. To improve the quantitative monitoring of progression and therapy of lung diseases in preclinical studies, we evaluated four different micro-CT-derived biomarkers describing longitudinal changes in normal development, lung infections, inflammation, fibrosis and therapy. Free-breathing mice underwent micro-CT before and repeatedly after induction of bleomycin-induced fibrosis, aspergillosis, cryptococcosis, therapy (imatinib) and pulmonary function tests. Total lung volume, aerated lung volume, tissue (lesion) volume and mean lung density were quantified and compared. All biomarkers changed continuously during follow-up of adult mouse lungs. Inflammation and fibrosis were quantified by aerated lung volume, tissue volume and mean lung density biomarkers, and lead to a substantial increase in total lung volume. Upon therapy of fibrotic lung disease, the improvement in aerated volume and function was not accompanied by a normalization of the total lung volume. Significantly enlarged lungs were also present in models of slowly and rapidly progressing lung infections. Our findings underscore the importance of quantifying total lung volume in addition to aerated lung or lesion volumes to accurately document lung pathology and potential compensatory mechanisms in mouse models, in order to fully describe and understand these dynamic processes. Longitudinal imaging and accurate quantification of disease progression and therapy effects are likely to improve the translatability of therapy trial results from mice to men.