title: Longitudinal micro-CT provides biomarkers of lung disease that can be used to assess the effect of therapy in preclinical mouse models, and reveal compensatory changes in lung volume.
abstract: In vivo lung micro-computed tomography (micro-CT) is being increasingly embraced in pulmonary research because it provides longitudinal information on dynamic disease processes in a field in which ex vivo assessment of experimental disease models is still the gold standard. To optimize the quantitative monitoring of progression and therapy of lung diseases, we evaluated longitudinal changes in four different micro-CT-derived biomarkers [aerated lung volume, lung tissue (including lesions) volume, total lung volume and mean lung density], describing normal development, lung infections, inflammation, fibrosis and therapy. Free-breathing mice underwent micro-CT before and repeatedly after induction of lung disease (bleomycin-induced fibrosis, invasive pulmonary aspergillosis, pulmonary cryptococcosis) and therapy (imatinib). The four lung biomarkers were quantified. After the last time point, we performed pulmonary function tests and isolated the lungs for histology. None of the biomarkers remained stable during longitudinal follow-up of adult healthy mouse lungs, implying that biomarkers should be compared with age-matched controls upon intervention. Early inflammation and progressive fibrosis led to a substantial increase in total lung volume, which affects the interpretation of aerated lung volume, tissue volume and mean lung density measures. Upon treatment of fibrotic lung disease, the improvement in aerated lung volume and function was not accompanied by a normalization of the increased total lung volume. Significantly enlarged lungs were also present in models of rapidly and slowly progressing lung infections. The data suggest that total lung volume changes could partly reflect a compensatory mechanism that occurs during disease progression in mice. Our findings underscore the importance of quantifying total lung volume in addition to aerated lung or lesion volumes to accurately document growth and potential compensatory mechanisms in mouse models of lung disease, in order to fully describe and understand dynamic processes during lung disease onset, progression and therapy. This is highly relevant for the translation of therapy evaluation results from preclinical studies to human patients.
authors.affiliation: Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, B-3000 Leuven, Flanders, Belgium.
authors.forename: Greetje
authors.initials: G
authors.lastname: Vande Velde
authors.affiliation: Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, B-3000 Leuven, Flanders, Belgium.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Poelmans
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, B-3000 Leuven, Flanders, Belgium Division of Rheumatology, University Hospitals Leuven, B-3000 Leuven, Flanders, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: De Langhe
authors.affiliation: Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, B-3000 Leuven, Flanders, Belgium.
authors.forename: Amy
authors.initials: A
authors.lastname: Hillen
authors.affiliation: Centre for Environment and Health, Department of Public Health and Primary Care, KU Leuven, B-3000 Leuven, Flanders, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Vanoirbeek
authors.affiliation: Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, B-3000 Leuven, Flanders, Belgium uwe.himmelreich@med.kuleuven.be.
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, B-3000 Leuven, Flanders, Belgium Division of Rheumatology, University Hospitals Leuven, B-3000 Leuven, Flanders, Belgium.
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Lories
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D001761:Bleomycin / Q000009:adverse effects; D003453:Cryptococcosis / Q000000981:diagnostic imaging; D004195:Disease Models, Animal; D005355:Fibrosis / Q000139:chemically induced / Q000000981:diagnostic imaging; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D007249:Inflammation; D008168:Lung / Q000000981:diagnostic imaging* / Q000473:pathology; D008171:Lung Diseases / Q000000981:diagnostic imaging* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055732:Pulmonary Aspergillosis / Q000000981:diagnostic imaging; D055114:X-Ray Microtomography / Q000379:methods*
chemical_list: D015415:Biomarkers; D001761:Bleomycin; D000068877:Imatinib Mesylate
keywords: Aspergillosis; Biomarkers; Bleomycin; Cryptococcosis; Disease models; In vivo; Infectious diseases; Lung inflammation; Lung volume; Micro-computed tomography; Pulmonary fibrosis; Quantification