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Longitudinal micro-computed tomography-derived biomarkers quantify non-resolving lung fibrosis in a silicosis mouse model

ABSTRACT: In spite of many compounds identified as antifibrotic in preclinical studies, pulmonary fibrosis remains a life-threatening condition for which highly effective treatment is still lacking. Towards improving the success-rate of bench-to-bedside translation, we investigated in vivo µCT-derived biomarkers to repeatedly quantify experimental silica-induced pulmonary fibrosis and assessed clinically relevant readouts up to several months after silicosis induction. Mice were oropharyngeally instilled with crystalline silica or saline and longitudinally monitored with respiratory-gated-high-resolution µCT to evaluate disease onset and progress using scan-derived biomarkers. At weeks 1, 5, 9 and 15, we assessed lung function, inflammation and fibrosis in subsets of mice in a cross-sectional manner. Silica-instillation increased the non-aerated lung volume, corresponding to onset and progression of inflammatory and fibrotic processes not resolving with time. Moreover, total lung volume progressively increased with silicosis. The volume of healthy, aerated lung first dropped then increased, corresponding to an acute inflammatory response followed by recovery into lower elevated aerated lung volume. Imaging results were confirmed by a significantly decreased Tiffeneau index, increased neutrophilic inflammation, increased IL-13, MCP-1, MIP-2 and TNF-? concentration in bronchoalveolar lavage fluid, increased collagen content and fibrotic nodules. µCT-derived biomarkers enable longitudinal evaluation of early onset inflammation and non-resolving pulmonary fibrosis as well as lung volumes in a sensitive and non-invasive manner. This approach and model of non-resolving lung fibrosis provides quantitative assessment of disease progression and stabilization over weeks and months, essential towards evaluation of fibrotic disease burden and antifibrotic therapy evaluation in preclinical studies.

SUBMITTER: Dekoster K

PROVIDER: S-EPMC7527558 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn vivo high-resolution micro-computed tomography allows for longitudinal image-based measurements in animal models of lung disease. The combination of repetitive high resolution imaging with fully automated quantitative image analysis in mouse models of lung fibrosis lung benefits preclinical research. This study aimed to develop and validate such an automated micro-computed tomography analysis algorithm for quantification of aerated lung volume in mice; an indicator of pulmonary fibrosis and emphysema severity.MethodologyMice received an intratracheal instillation of bleomycin (n = 8), elastase (0.25 U elastase n = 9, 0.5 U elastase n = 8) or saline control (n = 6 for fibrosis, n = 5 for emphysema). A subset of mice was scanned without intervention, to evaluate potential radiation-induced toxicity (n = 4). Some bleomycin-instilled mice were treated with imatinib for proof of concept (n = 8). Mice were scanned weekly, until four weeks after induction, when they underwent pulmonary function testing, lung histology and collagen quantification. Aerated lung volumes were calculated with our automated algorithm.Principal findingsOur automated image-based aerated lung volume quantification method is reproducible with low intra-subject variability. Bleomycin-treated mice had significantly lower scan-derived aerated lung volumes, compared to controls. Aerated lung volume correlated with the histopathological fibrosis score and total lung collagen content. Inversely, a dose-dependent increase in lung volume was observed in elastase-treated mice. Serial scanning of individual mice is feasible and visualized dynamic disease progression. No radiation-induced toxicity was observed. Three-dimensional images provided critical topographical information.ConclusionsWe report on a high resolution in vivo micro-computed tomography image analysis algorithm that runs fully automated and allows quantification of aerated lung volume in mice. This method is reproducible with low inherent measurement variability. We show that it is a reliable quantitative tool to investigate experimental lung fibrosis and emphysema in mice. Its non-invasive nature has the unique benefit to allow dynamic 4D evaluation of disease processes and therapeutic interventions.

Project description:This study used available or purchased equipment and an image reconstruction system developed by the college of dentistry to establish a basic self-assembled micro-computed tomography (micro-CT) system. Such a system would be suitable for teaching dental radiology to dental students. Specifically, it could help students to understand the principles governing dental cone-beam computed tomography (CBCT) and provide graduate students with a system for scanning small samples (e.g., individual teeth) during the early stages of research. The self-assembled micro-CT system was constructed using a portable dental X-ray tube, an intraoral digital X-ray detector, a high-precision rotation stage, related bracket accessories, and a notebook computer. Reconstructed images and three-dimensional models of the maxillary right third molar were produced using the self-assembled micro-CT system and an advanced commercially available micro-CT system (Skyscan 2211). Subsequently, the reconstructed images and 3D models produced using the two systems were compared by two senior dentists to determine whether considerable visual differences could be observed. Finally, the signal-to-noise ratio (SNR) was used for quantitative analysis and to compare the systems. Although the self-assembled micro-CT system produced image boundaries that were not as sharp as those of Skyscan 2211, the images were nonetheless remarkably similar. In addition, the two micro-CT systems produced 3D models that were almost identical in appearance and root canal shape. Quantitative analysis revealed that Skyscan 2211 had produced a SNR that was superior to that of the self-assembled micro-CT system, with the difference ranging from 36.77% to 136.22%; enamel, which has a higher density, exhibited lower SNR differences, whereas dentin, which has a lower density, exhibited higher SNR differences. The self-assembled micro-CT system with a resolution of 36 μm was created using a portable dental X-ray tube and an intraoral digital X-ray detector. Although the scanning time was relatively long (~30 min to scan images of a tooth), the images were adequate in the preliminary stage of experiments. More importantly, students were afforded the opportunity to observe the process of assembling and disassembling each component of a micro-CT scanner and thereby achieve a more comprehensive understanding of the principles governing micro-CT and dental CBCT.

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Longitudinal micro-computed tomography-derived biomarkers quantify non-resolving lung fibrosis in a silicosis mouse model

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