Hyaluronidase modulates bleomycin‐induced lung injury detected noninvasively in small rodents by radial proton MRI

Egger, Christine; Cannet, Catherine; Gérard, Christelle; Dunbar, Andrew; Tigani, Bruno; Beckmann, Nicolau

doi:10.1002/jmri.24612

Cited by 12 publications

(6 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, irrespective of which drug class that is investigated and what ILD pathology that can be mimicked in vivo, there is still a need for better imaging protocols and data analysis tools. Our method to define "high MRI signal" volume as the lesion, is histogram-based and avoid subjective decisions similar to the Lloyd-Max histogram quantitation used by many studies previously (Babin et al, 2011;Egger et al, 2013Egger et al, , 2014Egger et al, , 2015Egger et al, , 2017. We did not utilize the specific intensity of the MRI signal beyond finding a threshold, partly because we have not utilized an in-view standard to normalize the signal across measurement, as has been done in some other studies that include lung imaging (Shioya et al, 1993;Tournebize et al, 2006;Strobel et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Imaging Biomarkers and Pathobiological Profiling in a Rat Model of Drug-Induced Interstitial Lung Disease Induced by Bleomycin

Persson

Håkansson²,

Örbom

et al. 2020

Front. Physiol.

View full text Add to dashboard Cite

A large number of systemically administered drugs have the potential to cause druginduced interstitial lung disease (DIILD). We aim to characterize a model of DIILD in the rat and develop imaging biomarkers (IBs) for detection and quantification of DIILD. In this study, Sprague-Dawley rats received one single dose of intratracheal (i.t.) bleomycin and were longitudinally imaged at day 0, 3, 7, 14, 21, and 28 post dosing, applying the imaging techniques magnetic resonance imaging (MRI) and positron emission tomography (PET)/computed tomography (CT). Bronchoalveolar lavage fluid (BALF) was analyzed for total protein and inflammatory cells. Lungs were saved for further evaluation by gene analysis using quantitative-PCR and by histology. Lung sections were stained with Masson's-Trichrome staining and evaluated by modified Ashcroft score. Gene expression profiling of inflammatory and fibrotic markers was performed on lung tissue homogenates. Bleomycin induced significant increase in total protein concentration and total cell count in bronchoalveolar lavage (BAL), peaking at day 3 (p > 0.001) and day 7 (p > 0.001) compared to control, respectively. Lesions measured by MRI and PET signal in the lungs of bleomycin challenged rats were significantly increased during days 3-14, peaking at day 7. Two subgroups of animals were identified as low-and highresponders by their different change in total lung volume. Both groups showed signs of inflammation initially, while at later time points, the low-responder group recovered toward control, and the high-responder group showed sustained lung volume increase, and significant increase of lesion volume (p < 0.001) compared to control. Lastly, important inflammatory and pro-fibrotic markers were assessed from lung tissue, linking observed imaging pathological changes to gene expression patterns. In conclusion, bleomycin-induced lung injury is an adequate animal model for DIILD studies and for translational lung injury assessment by MRI and PET imaging. The scenario comprised disease responses, with different fractions of inflammation and fibrosis. Thereby, this study improved the understanding of imaging and biological biomarkers in DIILD and lung injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Imaging Biomarkers and Pathobiological Profiling in a Rat Model of Drug-Induced Interstitial Lung Disease Induced by Bleomycin

Persson

Håkansson²,

Örbom

et al. 2020

Front. Physiol.

View full text Add to dashboard Cite

show abstract

“…In abnormal tissues, as in pulmonary fibrosis, there is an excess of ECM and of proteoglycan proteins contained in this matrix. Proteoglycans are known to be hydrophilic and therefore could have a non‐negligible affinity with the nanoparticle solution . It can thus be hypothesized that passive transport of the nanoparticle solution is facilitated by the widespread presence of hydrophilic protein linked to collagen and ECM deposition in bleomycin‐induced lesions.…”

Section: Resultsmentioning

confidence: 99%

MR imaging, targeting and characterization of pulmonary fibrosis using intra‐tracheal administration of gadolinium‐based nanoparticles

Tassali

Bianchi

Lux

et al. 2016

Contrast Media & Molecular

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis is a devastating disease. Animal models are critical to develop new diagnostic approaches. We investigate here whether the application of an ultra-short echo time MRI sequence combined with the intra-tracheal administration of Gd-based nanoparticles can help to visualize and characterize pulmonary fibrosis in mice. 21 mice were imaged. Treated mice were administered bleomycin. MRI was used for longitudinal detection of bleomycin-induced lung injury from Day 1 up to Day 60. On Day 30, all mice received nanoparticles and MR images were acquired. A signal enhancement of 120% and 50% in fibrotic lesions and healthy tissues respectively was obtained. A twofold increase of contrast-to-noise ratio between fibrotic and healthy tissue was also observed, leading to a more accurate delineation of the extent of fibrosis. The elimination time constant of the nanoparticles was 54% higher in fibrotic lesions. Bleomycin-induced lung injury can be monitored using MRI. Intra-tracheal administration of Gd-based nanoparticles enabled us to enhance fibrotic tissue in lungs but also to extract imaging biomarkers that quantify elimination and diffusion of contrast agents and can characterize fibrotic tissue. The added value of MRI associated with pulmonary administration of contrast agents is key to better understand the lung fibrotic process and monitor drug response in pre-clinical studies, which will be valuable for translational applications. Copyright © 2016 John Wiley & Sons, Ltd.

show abstract

“…During fibrogenesis, fibroblasts will be induced (23)(24)(25), along with the increased production of components of the extracellular matrix (ECM), e.g., collagens, glycoproteins, fibronectin, and proteoglycans (13,26,27). Previously explored imaging biomarkers in the bleomycin model involved the assessment of lesions using MRI during inflammation and fibrosis, as well as PET tracers mapping disease progression in terms of increased uptake of [ 18 F]FDG and Collagen type I tracer uptake within the lung (28)(29)(30)(31)(32)(33)(34)(35). For tracking early-onset fibrosis, new emerging radiotracers for fibroblast activating protein (FAP) could be used to track the presence of activated fibroblasts in tissue (25,36).…”

Section: Introductionmentioning

confidence: 99%

Utilizing MRI, [18F]FDG-PET and [89Zr]Zr-DFO-28H1 FAP-PET tracer to assess inflammation and fibrogenesis in a reproducible lung injury rat model: a multimodal imaging study

Boswinkel,

Raavé,

Veltien

et al. 2023

Front. Nucl. Med.

View full text Add to dashboard Cite

ObjectiveAccurate imaging biomarkers that indicate disease progression at an early stage are highly important to enable timely mitigation of symptoms in progressive lung disease. In this context, reproducible experimental models and readouts are key. Here, we aim to show reproducibility of a lung injury rat model, by inducing disease and assessing disease progression by multi-modal non-invasive imaging techniques at two different research sites. Furthermore, we evaluated the potential of fibroblast activating protein (FAP) as an imaging biomarker in the early stage of lung fibrosis.MethodsAn initial lung injury rat model was set up at one research site (Lund University, Lund, Sweden) and repeated at a second site (Radboudumc, Nijmegen, The Netherlands). To induce lung injury, Sprague-Dawley rats received intratracheal instillation of bleomycin as one single dose (1,000 iU in 200 µL) or saline as control. Thereafter, longitudinal images were acquired to track inflammation in the lungs, at 1 and 2 weeks after the bleomycin challenge by magnetic resonance imaging (MRI) and [18F]FDG-PET. After the final [18F]FDG-PET scan, rats received an intravenous tracer [89Zr]Zr-DFO-28H1 (anti-FAP antibody) and were imaged at day 15, to track fibrogenesis. Upon termination, bronchoalveolar lavage (BAL) was performed to assess cell and protein concentration. Subsequently, the biodistribution of [89Zr]Zr-DFO-28H1 was measured ex vivo and the spatial distribution in lung tissue was studied by autoradiography. Lung sections were stained, and fibrosis assessed using the modified Ashcroft score.ResultsBleomycin-challenged rats showed body weight loss and increased numbers of immune cells and protein concentrations after BAL compared with control animals. The initiation and progression of the disease were reproduced at both research sites. Lung lesions in bleomycin-exposed rats were visualized by MRI and confirmed by histology. [18F]FDG uptake was higher in the lungs of bleomycin-challenged rats compared with the controls, similar to that observed in the Lund study. [89Zr]Zr-DFO-28H1 tracer uptake in the lung was increased in bleomycin-challenged rats compared with control rats (p = 0.03).ConclusionHere, we demonstrate a reproducible lung injury model and monitored disease progression using conventional imaging biomarkers MRI and [18F]FDG-PET. Furthermore, we showed the first proof-of-concept of FAP imaging. This reproducible and robust animal model and imaging experimental set-up allows for future research on new therapeutics or biomarkers in lung disease.

show abstract

Hyaluronidase modulates bleomycin‐induced lung injury detected noninvasively in small rodents by radial proton MRI

Abstract: The present data indicate that hyaluronic acid contributes to the bleomycin-induced responses detected by MRI in the lung.

Cited by 12 publications

References 43 publications

Imaging Biomarkers and Pathobiological Profiling in a Rat Model of Drug-Induced Interstitial Lung Disease Induced by Bleomycin

Imaging Biomarkers and Pathobiological Profiling in a Rat Model of Drug-Induced Interstitial Lung Disease Induced by Bleomycin

MR imaging, targeting and characterization of pulmonary fibrosis using intra‐tracheal administration of gadolinium‐based nanoparticles

Utilizing MRI, [18F]FDG-PET and [89Zr]Zr-DFO-28H1 FAP-PET tracer to assess inflammation and fibrogenesis in a reproducible lung injury rat model: a multimodal imaging study

Contact Info

Product

Resources

About