Name: a multimodal imaging approach based on micro-ct and fluorescence molecular tomography for longitudinal assessment of bleomycin-induced lung fibrosis in mice
Uploaded: 2018-04-13T12:30:00
Description: Watch this Scientific Journal Video about A Multimodal Imaging Approach Based on Micro-CT and Fluorescence Molecular Tomography for Longitudinal Assessment of Bleomycin-Induced Lung Fibrosis in Mice a

The authors would like to thank Dr. Daniela Pompilio and Roberta Ciccimarra for technical help.

All animal experiments described herein were approved by the intramural animal-welfare committee for animal experimentation of Chiesi Farmaceutici and ERASMUS MC under protocol number: EMC 3349 (138-14-07) complying with the European Directive 2010/63 UE, Italian D.Lgs 26/2014 and the revised &#34;Guide for the Care and Use of Laboratory Animals&#34;23.
NOTE: Prior to use, female inbred C57Bl/6 (7-8 weeks old) mice were acclimatized for at least 7 days to the local viva...

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Despite many research groups focusing on developing new drugs to treat IPF, at the moment only two are available for patients. There is an urgent medical need to find more effective therapies7 because only lung transplantationis able to prolong survival of 4-5 years26. The essential prerequisite for translational medicine and development of new drugs is the availability of an animal model that mimics the features of IPF and in which interventional studies are predictive of ...

Idiopathic pulmonary fibrosis (IPF) is chronic lung disease with progressive decrease of lung functions that is unfortunately often fatal within four years of diagnosis1. The major features of IPF are extracellular matrix deposition and fibroblast proliferation, but the pathogenesis is not yet fully understood. The most supported hypothesis is that multiple cycles of lung injuries cause the destruction of alveolar epithelial cells that leads to alteration of the mesenchymal cell cycle proliferation, exaggerated accumulation of fibroblasts and myofibroblasts, and increased matrix production. Mediators involved in these processes such as matrix metalloproteinases (MMPs) have been found dysregulated in fibrosis development either in human IPF or in bleomycin-induced animal models. The uncontrolled MMP production leads to an unbalanced collagen deposition within the lung interstitium and alveolar space, mimicking abnormal wound repair1,2.
One of the main obstacles for drug discovery and development is the availability of accessible mouse models that mimic human pathogenesis and the disease phenotype. Different agents have been used to induce lung fibrosis in animal models: irradiation damage, administration of asbestos and silica, administration of fibrinogenic cytokines and bleomycin3,4; however bleomycin is the most used in mice, rats, guinea pigs, hamsters, rabbits5 or in large animals (non-human primates, horses, dogs and ruminants)6,7. Bleomycin is an antibiotic made by the bacterium Streptomyces verticillus8 and is used as an anti-cancer agent9. Pulmonary fibrosis is a common side effect of the drug and for this reason, it is used in experimental animal models to induce pulmonary fibrosis.
In bleomycin-induced lung fibrosis models, the fibrotic lesions occur 14 - 21 days after bleomycin administration. In the presented work, we used a new protocol to induce lung fibrosis in mice by double bleomycin intratracheal instillation. The bleomycin mouse model is very time consuming because new drugs need to be evaluated on established fibrotic lesions, and tested to distinguish their anti-fibrotic effects from anti-inflammatory effects.
Biochemical determination of collagen content, morphometrical and histological analysis were based on post mortem analysis, limiting the possibility to follow the pathogenesis of the disease in the same animal. Although these parameters were considered a gold standard for fibrosis evaluation, they did not provide any temporal or spatial distribution of the fibrotic lesion and preclude a way to investigate the process of disease progression.10
Recently, non-invasive imaging technologies have been applied to monitor airway remodeling, inflammation, and fibrosis progression in murine models: Magnetic Resonance Imaging (MRI), Micro Computer Tomography (Micro-CT), Fluorescence Molecular Tomography (FMT) and Bioluminescent (BLI)11,12,13,14,15,16,17,18,19,20,21. We propose a non-invasive imaging approach to monitor longitudinally lung fibrosis progression by FMT and Micro-CT at different time-points after a bleomycin challenge22.
Many pathways are involved in the establishment and development of fibrosis, and not much is known. Only a deeper understanding of these processes could translate to more drug targets that may transfer into the clinic. The ability to longitudinally monitor MMP activation by fluorescence molecular tomography coupled to the detection of lung parenchymal changes by Micro-CT might be used in the future to access the clinical response to treatment.

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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

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the progressive and irreversible destruction of lung architecture, which causes significant deterioration in lung function and subsequent death from respiratory failure.
The pathogenesis of IPF in experimental animal models has been induced by bleomycin administration. In this study, we investigate an IPF-like mouse model induced by a double intratracheal bleomycin instillation. Standard histological assessments used for studying lung fibrosis are invasive terminal procedures. The goal of this work is to monitor lung fibrosis through noninvasive imaging techniques such as Fluorescent Molecular Tomography (FMT) and Micro-CT. These two technologies validated with histology findings could represent a revolutionary functional approach for real time non-invasive monitoring of IPF disease severity and progression. The fusion of different approaches represents a step further for understanding the IPF disease, where the molecular events occurring in a pathological condition can be observed with FMT and the subsequent anatomical changes can be monitored by Micro-CT.

Spontaneous resolution of the lung fibrosis lesions observed three weeks after single bleomycin administration and moderate structural changes highlight the limits of this model. Only preventive treatment could be performed due to the narrow therapeutic window that does not represent clinical practice17.
Here, we demonstrate that our protocol of double bleomycin intratracheal instillation is able to devel...

Watch this Scientific Journal Video about A Multimodal Imaging Approach Based on Micro-CT and Fluorescence Molecular Tomography for Longitudinal Assessment of Bleomycin-Induced Lung Fibrosis in Mice a

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

We describe a non-invasive multimodal imaging approach based on Micro-CT and fluorescence molecular tomography for longitudinal assessment of the mouse lung fibrosis model induced by double intratracheal instillation of bleomycin.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the progressive and irreversible destruction of lung architecture, which ...

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