Abstract
Idiopathic pulmonary fibrosis is a very common interstitial lung disease derived from chronic inflammatory insults, characterized by massive scar tissue deposition that causes the progressive loss of lung function and subsequent death for respiratory failure. Bleomycin is used as the standard agent to induce experimental pulmonary fibrosis in animal models for the study of its pathogenesis. However, to visualize the establishment of lung fibrosis after treatment, the animal sacrifice is necessary. Thus, the aim of this study was to avoid this limitation by using an innovative approach based on a double bleomycin treatment protocol, along with the in vivo images analysis of bleomycin-treated mice. A reporter gene construct, containing the luciferase open reading frame under the matrix metalloproteinase-1 promoter control region, was tested on double bleomycin-treated mice to investigate, in real time, the correlation between bleomycin treatment, inflammation, tissue remodeling and fibrosis. Bioluminescence emitted by the lungs of bleomycin-treated mice, corroborated by fluorescent molecular tomography, successfully allowed real time monitoring of fibrosis establishment. The reporter gene technology experienced in this work could represent an advanced functional approach for real time non-invasive assessment of disease evolution during therapy, in a reliable and translational living animal model.
Highlights
Idiopathic pulmonary fibrosis (IPF), the most common of the idiopathic interstitial pneumonias, is a devastating condition that carries a prognosis worse than that of many cancers
A better understanding of the pathogenesis of IPF is critical for the identification of new therapeutic targets as well as molecules that may serve as surrogate markers for clinically significant endpoints
Other imaging technologies have been used to follow the establishment of lung fibrosis in real time, such as micro-CT, PET, MRI, and cathepsin-activated fluorescent probes [9,10,11], we propose an innovative and easy in vivo bioluminescent imaging (BLI) approach for drug discovery purpose
Summary
Idiopathic pulmonary fibrosis (IPF), the most common of the idiopathic interstitial pneumonias, is a devastating condition that carries a prognosis worse than that of many cancers. Different models have been built over time to examine pulmonary fibrosis. These methods include radiation damage, administration of asbestos and silica, and administration of fibrinogenic cytokines and bleomycin [3]. This later method became the standard agent to induce experimental pulmonary fibrosis in animals such as small laboratory animals (including mice, rats, guinea pigs, hamsters, and rabbits) [3, 4] and large animals (including non-human primates, horses, dogs, and ruminants) [3, 5, 6]. Its use in animal models of pulmonary fibrosis is based on the fact that fibrosis is a side effect of this agent in human cancer therapy [8]
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