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Longitudinal free-breathing MRI measurement of murine lung physiology in a progressive model of lung fibrosis.

ABSTRACT: To longitudinally monitor progressive fibrosis in the transforming growth factor-? (TGF-?) transgenic mouse model of lung fibrosis, we used retrospective self-gating ultrashort echo time (UTE) magnetic resonance imaging (MRI) to image mouse lung at baseline and after 4 and 8 wk of fibrosis initiation via doxycycline administration. Only bitransgenic mice were used in this study and divided into two cohorts: six mice were fed doxycycline food to induce lung fibrosis (referred to as Dox cohort), and five other mice were fed normal food (referred to as control cohort). Lung mechanics, histology, and hydroxyproline were assessed after the final MRI. A linear mixed-effects model was used to analyze MRI-derived longitudinal lung-function parameters. Tidal volume decreased at a rate of -0.016?±?0.002 ml/week [?2(1)?=?16.48, P < 0.001] for Dox cohort and increased at a rate of 0.010?±?0.003 ml/week [?2(1)?=?6.37, P = 0.01] for control cohort. Minute ventilation decreased at a rate of -1.71?±?0.26 ml·min-1·wk-1 [?2(1)?=?14.04, P < 0.001] for Dox cohort but did not change significantly over time for control cohort. High-density lung volume percentage increased at a rate of 3.9 ± 0.7%/wk for Dox cohort [?2(1)?=?11.47, P < 0.001] but did not change significantly over time for control cohort. MRI-derived lung structure and function parameters were strongly correlated with pleural thickness, hydroxyproline content, lung compliance, airway resistance, and airway elastance. We conclude that self-gating UTE MRI could be used to longitudinally monitor lung fibrosis in the TGF-? transgenic mouse model. NEW & NOTEWORTHY Self-gating UTE MRI was used to monitor morphology and physiology in lung fibrosis in a transforming growth factor-? transgenic mouse model. Tidal volume was shown for the first time to correlate strongly with conventional metrics of fibrosis such as hydroxyproline and pleural thickness.

SUBMITTER: Guo J

PROVIDER: S-EPMC6485694 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Longitudinal free-breathing MRI measurement of murine lung physiology in a progressive model of lung fibrosis.

Guo Jinbang J Hardie William D WD Cleveland Zackary I ZI Davidson Cynthia C Xu Xuefeng X Madala Satish K SK Woods Jason C JC

Journal of applied physiology (Bethesda, Md. : 1985) 20190207 4

To longitudinally monitor progressive fibrosis in the transforming growth factor-α (TGF-α) transgenic mouse model of lung fibrosis, we used retrospective self-gating ultrashort echo time (UTE) magnetic resonance imaging (MRI) to image mouse lung at baseline and after 4 and 8 wk of fibrosis initiation via doxycycline administration. Only bitransgenic mice were used in this study and divided into two cohorts: six mice were fed doxycycline food to induce lung fibrosis (referred to as Dox cohort), a ...[more]

PMID: 30730810

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Project description:Lung fibrosis (LF) is a chronic progressive, incurable, and debilitating condition of the lung, which is associated with different lung disease. Treatment options are still sparse. Nintedanib, an oral tyrosine kinase inhibitor, significantly slows the LF progression. However, there is a strong need of further research and the development of novel therapies. In this study, we used a correlative set-up that combines X-ray based lung function (XLF) with microCT and whole body plethysmography (WBP) for a comprehensive functional and structural evaluation of lung fibrosis (LF) as well as for monitoring response to orally administered Nintedanib in the mouse model of bleomycin induced LF. The decline in lung function as early as one week after intratracheal bleomycin instillation was reliably detected by XLF, revealing the lowest decay rate in the LF mice compared to healthy ones. Simultaneously performed microCT and WBP measurements corroborated XLF findings by exhibiting reduced lung volume [Formula: see text] and tidal volume [Formula: see text]. In LF mice XLF also revealed profound improvement in lung function one week after Nintedanib treatment. This positive response to Nintedanib therapy was further substantiated by microCT and WBP measurements which also showed significantly improved [Formula: see text] and [Formula: see text] in the Nintedanib treated mice. By comparing the XLF data to structural features assessing the extent of fibrosis obtained by ex-vivo high-resolution synchrotron radiation-based imaging and classical histology we demonstrate that: (1) a simple low dose x-ray measurement like XLF is sensitive enough to pick up treatment response, (2) Nintedanib treatment successfully improved lung function in a bleomycin induced LF mouse model and (3) differences between the fully restored lung function and the partially reduced fibrotic burden compared to healthy and untreated mice. The presented analysis pipeline underlines the importance of a combined functional and anatomical readout to reliably measure treatment response and could easily be adapted to other preclinical lung disease models.

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Dataset Information

Longitudinal free-breathing MRI measurement of murine lung physiology in a progressive model of lung fibrosis.

Publications

Longitudinal free-breathing MRI measurement of murine lung physiology in a progressive model of lung fibrosis.

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