Preclinical anatomical, molecular, and functional imaging of the lung with multiple modalities

Gammon, Seth T.; Foje, Nathan; Brewer, Elizabeth M.; Owers, Elizabeth; Downs, Charles A.; Budde, Matthew D.; Leevy, W. Matthew; Helms, My N.

doi:10.1152/ajplung.00007.2014

Cited by 29 publications

(26 citation statements)

References 155 publications

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“…Hounsfield unit (HU) histograms were obtained for left and right lungs using bins of 10-HU width. In the absence of a well-established gold standard to quantify fibrotic changes in rodents with micro-CT and to avoid relying on an arbitrary threshold to identify fibrotic regions [14,15] the HU corresponding to the peak of the HU-histogram for the segmented pixels were used as a measure of the progression of fibrosis. Total lung volume was also computed.…”

Section: Methodsmentioning

confidence: 99%

Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis

Gilhodes¹,

Julé²,

Kreuz

et al. 2017

PLoS ONE

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Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between different laboratories. To achieve a reliable and observer-independent quantification of lung fibrosis we developed an automated software histological image analysis performed from digital image of entire lung sections. This automated analysis was compared to standard evaluation methods with regard to its validation as an end-point measure of fibrosis. Lung fibrosis was induced in mice by intratracheal administration of bleomycin (BLM) at 0.25, 0.5, 0.75 and 1 mg/kg. A detailed characterization of BLM-induced fibrosis was performed 14 days after BLM administration using lung function testing, micro-computed tomography and Ashcroft scoring analysis. Quantification of fibrosis by automated analysis was assessed based on pulmonary tissue density measured from thousands of micro-tiles processed from digital images of entire lung sections. Prior to analysis, large bronchi and vessels were manually excluded from the original images. Measurement of fibrosis has been expressed by two indexes: the mean pulmonary tissue density and the high pulmonary tissue density frequency. We showed that tissue density indexes gave access to a very accurate and reliable quantification of morphological changes induced by BLM even for the lowest concentration used (0.25 mg/kg). A reconstructed 2D-image of the entire lung section at high resolution (3.6 μm/pixel) has been performed from tissue density values allowing the visualization of their distribution throughout fibrotic and non-fibrotic regions. A significant correlation (p<0.0001) was found between automated analysis and the above standard evaluation methods. This correlation establishes automated analysis as a novel end-point measure of BLM-induced lung fibrosis in mice, which will be very valuable for future preclinical drug explorations.

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Section: Methodsmentioning

confidence: 99%

Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis

Gilhodes¹,

Julé²,

Kreuz

et al. 2017

PLoS ONE

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“…There are two invasive methods, Buxcoforce pulmonary maneuvers, and FlexiVent, which allow the measurement of several functional tests of clinical relevance for lung fibrosis, such as pressure-volume curves (66). With forced oscillation techniques, lung impedance can be examined and, through it, several variables, such as lung tissue elastance and tissue damping (54,66,67). Some studies suggest that values obtained by forced oscillation techniques correlate better with extent of fibrosis than do pressure-volume curves (47,54).…”

Section: Lung Functionmentioning

confidence: 99%

“…Multiple techniques have been developed to acquire functional, molecular, and/or anatomical images of the body, including bioluminescence, fluorescence, magnetic resonance imaging, planar X-ray, X-ray computed tomography (CT), nuclear imaging with positron emission tomography, and single-photon emission CT (SPECT) (67). However, experience with most of these methods in animal models of lung fibrosis is scant.…”

Section: Imagingmentioning

confidence: 99%

An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis

Jenkins

Moore

Chambers

et al. 2017

Am J Respir Cell Mol Biol

316

254

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Numerous compounds have shown efficacy in limiting development of pulmonary fibrosis using animal models, yet few of these compounds have replicated these beneficial effects in clinical trials. Given the challenges associated with performing clinical trials in patients with idiopathic pulmonary fibrosis (IPF), it is imperative that preclinical data packages be robust in their analyses and interpretations to have the best chance of selecting promising drug candidates to advance to clinical trials. The American Thoracic Society has convened a group of experts in lung fibrosis to discuss and formalize recommendations for preclinical assessment of antifibrotic compounds. The panel considered three major themes (choice of animal, practical considerations of fibrosis modeling, and fibrotic endpoints for evaluation). Recognizing the need for practical considerations, we have taken a pragmatic approach. The consensus view is that use of the murine intratracheal bleomycin model in animals of both genders, using hydroxyproline measurements for collagen accumulation along with histologic assessments, is the best-characterized animal model available for preclinical testing. Testing of antifibrotic compounds in this model is recommended to occur after the acute inflammatory phase has subsided (generally after Day 7). Robust analyses may also include confirmatory studies in human IPF specimens and validation of results in a second system using in vivo or in vitro approaches. The panel also strongly encourages the publication of negative results to inform the lung fibrosis community. These recommendations are for preclinical therapeutic evaluation only and are not intended to dissuade development of emerging technologies to better understand IPF pathogenesis.

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“…Since 1999, molecular imaging proposed by Weissleder [1] has been continuously evolving and contributing to biomedical research and applications [2,3]. Imaging agents targeting specific biomarkers or molecular processes provide distinctive physiological and pathological information, and they enable imaging modalities and strategies to realize the capability which were impossible several years ago.…”

Section: Introductionmentioning

confidence: 99%

In vivo pentamodal tomographic imaging for small animals

Liu¹,

Guo²,

Liu³

et al. 2017

Biomed. Opt. Express

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Multimodality molecular imaging emerges as a powerful strategy for correlating multimodal information. We developed a pentamodal imaging system which can perform positron emission tomography, bioluminescence tomography, fluorescence molecular tomography, Cerenkov luminescence tomography and X-ray computed tomography successively. Performance of sub-systems corresponding to different modalities were characterized. In vivo multimodal imaging of an orthotopic hepatocellular carcinoma xenograft mouse model was performed, and acquired multimodal images were fused. The feasibility of pentamodal tomographic imaging system was successfully validated with the imaging application on the mouse model. The ability of integrating anatomical, metabolic, and pharmacokinetic information promises applications of multimodality molecular imaging in precise medicine. Som, C. N. Wan, A. P. Wolf, D. E. Kuhl, and M. Reivich, "Radiopharmaceuticals XXVII. 18F-labeled 2-deoxy-2-fluoro-d-glucose as a radiopharmaceutical for measuring regional myocardial glucose metabolism in vivo: tissue distribution and imaging studies in animals," J. Nucl. Med. 18(10), 990-996 (1977).

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Preclinical anatomical, molecular, and functional imaging of the lung with multiple modalities

Cited by 29 publications

References 155 publications

Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis

Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis

An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis

In vivo pentamodal tomographic imaging for small animals

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