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
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 quantitat...
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doaj-ef47be56f1044a5ba48e802945d6acbc2020-11-25T02:21:58ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032016-01-0191919810.1242/dmm.020321020321Longitudinal 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 volumeGreetje Vande Velde0Jennifer Poelmans1Ellen De Langhe2Amy Hillen3Jeroen Vanoirbeek4Uwe Himmelreich5Rik J. Lories6 Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, B-3000 Leuven, Flanders, Belgium Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, B-3000 Leuven, Flanders, Belgium Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, B-3000 Leuven, Flanders, Belgium Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, B-3000 Leuven, Flanders, Belgium Centre for Environment and Health, Department of Public Health and Primary Care, KU Leuven, B-3000 Leuven, Flanders, Belgium Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, B-3000 Leuven, Flanders, Belgium Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, B-3000 Leuven, Flanders, Belgium 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.http://dmm.biologists.org/content/9/1/91QuantificationPulmonary fibrosisLung inflammationInfectious diseasesMicro-computed tomographyIn vivoLung volumeDisease modelsBiomarkersBleomycinAspergillosisCryptococcosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Greetje Vande Velde Jennifer Poelmans Ellen De Langhe Amy Hillen Jeroen Vanoirbeek Uwe Himmelreich Rik J. Lories |
spellingShingle |
Greetje Vande Velde Jennifer Poelmans Ellen De Langhe Amy Hillen Jeroen Vanoirbeek Uwe Himmelreich Rik J. Lories 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 Disease Models & Mechanisms Quantification Pulmonary fibrosis Lung inflammation Infectious diseases Micro-computed tomography In vivo Lung volume Disease models Biomarkers Bleomycin Aspergillosis Cryptococcosis |
author_facet |
Greetje Vande Velde Jennifer Poelmans Ellen De Langhe Amy Hillen Jeroen Vanoirbeek Uwe Himmelreich Rik J. Lories |
author_sort |
Greetje Vande Velde |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8411 1754-8403 |
publishDate |
2016-01-01 |
description |
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. |
topic |
Quantification Pulmonary fibrosis Lung inflammation Infectious diseases Micro-computed tomography In vivo Lung volume Disease models Biomarkers Bleomycin Aspergillosis Cryptococcosis |
url |
http://dmm.biologists.org/content/9/1/91 |
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