A Multimodal Imaging Approach Based on Micro-CT and Fluorescence Molecular Tomography for Longitudinal Assessment of Bleomycin-Induced Lung Fibrosis in Mice

Ruscitti, Francesca; Ravanetti, Francesca; Donofrío, Gaetano; Ridwan, Yanto; Heijningen, Paula van; Essers, Jeroen; Villetti, Gino; Cacchioli, Antonio; Vos, Wim; Stellari, Fabio

doi:10.3791/56443

Cited by 17 publications

(19 citation statements)

References 26 publications

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“…In our study, CT quantification detected fibrotic changes in the lungs of BLM-receiving mice from D9 with progression up to D23 in correlation with classical histological determination of lung collagen content in this preclinical model. Our results are in accordance with previous studies demonstrating that lung CT imaging segmentation and quantification using equivalent methods were in good agreement with histological read-outs and were able to quantify effectively and non-invasively disease progression longitudinally in several lung fibrosis models [21][22][23]. Furthermore, we demonstrate that our CT imaging lung segmentation/quantification allowed the monitoring of pirfenidone and nintedanib anti-fibrotic efficacy by reducing MLD and increasing lung aerated areas from D9 up to D23.…”

Section: Discussionsupporting

confidence: 91%

[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach

Tanguy

Goirand

Bouchard

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [18F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [18F]FDG. Methods Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [18F]FDG and [18F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23. Results We demonstrate that mean lung density on CT as well as [18F]FDG and [18F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [18F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [18F]FDG and [18F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [18F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy. Conclusion [18F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.

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Section: Discussionsupporting

confidence: 91%

[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach

Tanguy

Goirand

Bouchard

et al. 2021

Eur J Nucl Med Mol Imaging

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“…Animals were lightly anesthetized with 2.5% isoflurane delivered in a box and bleomycin hydrochloride BAXTER (1 mg/kg) in 50 µl of saline (0.9%) or vehicle [50 µl of saline (0.9%)] was instilled directly through a tracheal cannula, using a small laryngoscope (Penn-Century Inc., Philadelphia, PA, USA) to visualize the trachea ( Ruscitti et al., 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…In humans, longitudinal characterization of lung fibrotic diseases extent and progression by noninvasive imaging techniques, such as high-resolution computed tomography (HRCT) ( Lynch et al., 2018 ; Raghu et al., 2018 ; Sverzellati et al., 2018 ; Wu et al., 2018 ), magnetic resonance imaging (MRI) ( Weatherley et al., 2018 ; Wild, 2018 ), and positron emission tomography (PET) ( Justet et al., 2017 ; Win et al., 2018 ), is now well established. Recently, these techniques with the prefix of “Micro” (CT, PET and MRI) have been optimized and validated to assess lung fibrosis at different time points in living animals and so that each subject can act as their own control ( Egger et al., 2013 ; Egger et al., 2014 ; Withana et al., 2016 ; Désogère et al., 2017 ; Ruscitti et al., 2017 ; Ruscitti et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Quantification of Lung Fibrosis in IPF-Like Mouse Model and Pharmacological Response to Treatment by Micro-Computed Tomography

et al. 2020

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive degenerative lung disease leading to respiratory failure and death. Although anti-fibrotic drugs are now available for treating IPF, their clinical efficacy is limited and lung transplantation remains the only modality to prolong survival of IPF patients. Despite its limitations, the bleomycin (BLM) animal model remains the best characterized experimental tool for studying disease pathogenesis and assessing efficacy of novel potential drugs. In the present study, the effects of oropharyngeal (OA) and intratracheal (IT) administration of BLM were compared in C57BL/6 mice. The development of lung fibrosis was followed in vivo for 28 days after BLM administration by micro-computed tomography and ex vivo by histological analyses (bronchoalveolar lavage, histology in the left lung to stage fibrosis severity and hydroxyproline determination in the right lung). In a separate study, the antifibrotic effect of Nintedanib was investigated after oral administration (60 mg/kg for two weeks) in the OA BLM model. Lung fibrosis severity and duration after BLM OA and IT administration was comparable. However, a more homogeneous distribution of fibrotic lesions among lung lobes was apparent after OA administration. Quantification of fibrosis by micro-CT based on % of poorly aerated tissue revealed that this readout correlated significantly with the standard histological methods in the OA model. These findings were further confirmed in a second study in the OA model, evaluating Nintedanib anti-fibrotic effects. Indeed, compared to the BLM group, Nintedanib inhibited significantly the increase in % of poorly aerated areas (26%) and reduced ex vivo histological lesions and hydroxyproline levels by 49 and 41%, respectively. This study indicated that micro-computed tomography is a valuable in vivo technology for lung fibrosis quantification, which will be very helpful in the future to better evaluate new anti-fibrotic drug candidates.

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“…Recently, micro-CT imaging has been applied in some animal models of lung diseases including fibrosis and emphysema ( 3 – 5 ), emerging as a powerful tool for the longitudinal assessment of disease progression ( 2 , 3 , 6 ). However, translating CT technique to pre-clinical research has some challenging issues, namely due to the small size of rodents and their rapid respiratory cycle ( 3 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

Alfaxalone and Dexmedetomidine as an Alternative to Gas Anesthesia for Micro-CT Lung Imaging in a Bleomycin-Induced Pulmonary Fibrosis Murine Model

et al. 2020

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Micro-CT imaging could be considered a powerful non-invasive tool for accessing pulmonary fibrosis in mice. However, the choice of the anesthesia protocol plays a fundamental role to obtain robust and reproducible data, avoiding misinterpretations of the results. Inhaled anesthesia is commonly used for micro-CT lung imaging, but sometimes the standardization of the protocol may be challenging for routine activities in drug discovery. In this study we used micro-CT to evaluate the effects of two anesthetic protocols, consisting in Alfaxalone and Dexmedetomidine mixture, as injectable agents, and gaseous isoflurane, on vehicle and bleomycin-treated mice. No significant differences were highlighted between the protocols either for lung aeration degrees by micro-CT or histologic analyses in both the controls and bleomycin-treated groups. Our results support Alfaxalone and Dexmedetomidine mixture as a suitable and safe alternative compared to isoflurane for lung imaging. We also concluded that this injectable mixture may be applied for several imaging technologies and on different mice models.

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A Multimodal Imaging Approach Based on Micro-CT and Fluorescence Molecular Tomography for Longitudinal Assessment of Bleomycin-Induced Lung Fibrosis in Mice

Cited by 17 publications

References 26 publications

[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach

[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach

Quantification of Lung Fibrosis in IPF-Like Mouse Model and Pharmacological Response to Treatment by Micro-Computed Tomography

Alfaxalone and Dexmedetomidine as an Alternative to Gas Anesthesia for Micro-CT Lung Imaging in a Bleomycin-Induced Pulmonary Fibrosis Murine Model

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