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In-vivo lung fibrosis staging in a bleomycin-mouse model: a new micro-CT guided densitometric approach.

ABSTRACT: Although increasing used in the preclinical testing of new anti-fibrotic drugs, a thorough validation of micro-computed tomography (CT) in pulmonary fibrosis models has not been performed. Moreover, no attempts have been made so far to define density thresholds to discriminate between aeration levels in lung parenchyma. In the present study, a histogram-based analysis was performed in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis by micro-CT, evaluating longitudinal density changes from 7 to 21 days after BLM challenge, a period representing the progression of fibrosis. Two discriminative densitometric indices (i.e. 40th and 70th percentiles) were extracted from Hounsfield Unit density distributions and selected for lung fibrosis staging. The strong correlation with histological findings (r_Spearman?=?0.76, p?Spearman?=?0.6, p?

SUBMITTER: Mecozzi L

PROVIDER: S-EPMC7603396 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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In-vivo lung fibrosis staging in a bleomycin-mouse model: a new micro-CT guided densitometric approach.

Mecozzi Laura L Mambrini Martina M Ruscitti Francesca F Ferrini Erica E Ciccimarra Roberta R Ravanetti Francesca F Sverzellati Nicola N Silva Mario M Ruffini Livia L Belenkov Sasha S Civelli Maurizio M Villetti Gino G Stellari Fabio Franco FF

Scientific reports 20201030 1

Although increasing used in the preclinical testing of new anti-fibrotic drugs, a thorough validation of micro-computed tomography (CT) in pulmonary fibrosis models has not been performed. Moreover, no attempts have been made so far to define density thresholds to discriminate between aeration levels in lung parenchyma. In the present study, a histogram-based analysis was performed in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis by micro-CT, evaluating longitudinal density changes ...[more]

PMID: 33127949

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Project description:Interventions for bone diseases (e.g. osteoporosis) require testing in animal models before clinical translation and the mouse tibia is among the most common tested anatomical sites. In vivo micro-Computed Tomography (microCT) based measurements of the geometrical and densitometric properties are non-invasive and therefore constitute an important tool in preclinical studies. Moreover, validated micro-Finite Element (microFE) models can be used for predicting the bone mechanical properties non-invasively. However, considering that the image processing pipeline requires operator-dependant steps, the reproducibility of these measurements has to be assessed. The aim of this study was to evaluate the intra- and inter-operator reproducibility of several bone parameters measured from microCT images. Ten in vivo microCT images of the right tibia of five mice (at 18 and 22 weeks of age) were processed. One experienced operator (intra-operator analysis) and three different operators (inter-operator) aligned each image to a reference through a rigid registration and selected a volume of interest below the growth plate. From each image the following parameters were measured: total bone mineral content (BMC) and density (BMD), BMC in 40 subregions (ten longitudinal sections, four quadrants), microFE-based stiffness and failure load. Intra-operator reproducibility was acceptable for all parameters (precision error, PE < 3.71%), with lowest reproducibility for stiffness (3.06% at week 18, 3.71% at week 22). The inter-operator reproducibility was slightly lower (PE < 4.25%), although still acceptable for assessing the properties of most interventions. The lowest reproducibility was found for BMC in the lateral sector at the midshaft (PE = 4.25%). Densitometric parameters were more reproducible than most standard morphometric parameters calculated in the proximal trabecular bone. In conclusion, microCT and microFE models provide reproducible measurements for non-invasive assessment of the mouse tibia properties.

Project description:Background and aimsIdiopathic pulmonary fibrosis (IPF) is a fibrosing lung disease with unknown etiology, leading to cough and dyspnoea, which is also one of the most common sequelae affecting the quality of life of COVID-19 survivors. There is no cure for IPF patients. We aim to develop a reliable IPF animal model with quantification of fibrosis based on Micro-Computer Tomography (micro-CT) images for the new drug discovery, because different bleomycin administration routes, doses, and intervals are reported in the literature, and there is no quantitative assessment of pulmonary fibrosis based on micro-CT images in animal studies.MethodsWe compared three dosages (1.25 mg/kg, 2.5 mg/kg, and 5 mg/kg) of intratracheal bleomycin administration and experiment intervals (14 and 21 days) in C57BL/6 mice by investigating survival rates, pulmonary histopathology, micro-CT, peripheral CD4+ & CD8+ cells, and cytokines. Moreover, a simple and reliable new method was developed for scoring fibrosis in live mice based on Micro-CT images by using Image J software, which transfers the dark sections in pulmonary Micro-CT images to light colors on a black background.ResultsThe levels of hydroxyproline, inflammation cytokine, fibrotic pathological changes, and collagen deposition in the lungs of mice were bleomycin dose-dependent and time-dependent as well as the body weight loss. Based on the above results, the mice model at 21 days after being given bleomycin at 1.25 mg/kg has optimal pulmonary fibrosis with a high survival rate and low toxicity. There is a significant decrease in the light area (gray value at 9.86 ± 0.72) in the BLM mice, indicating that a significant decrease in the alveolar air area was observed in BLM injured mice compared to normal groups (###p < 0.001), while the Pirfenidone administration increased the light area (gray value) to 21.71 ± 2.95 which is close to the value observed in the normal mice (gray value at 23.23 ± 1.66), which is consistent with the protein levels of Col1A1, and α-SMA. Notably, the standard deviations for the consecutive six images of each group indicate the precision of this developed quantitation method for the micro-CT image taken at the fifth rib of each mouse.ConclusionProvided a quantifying method for Micro-CT images in an optimal and repeatable pulmonary fibrosis mice model for exploring novel therapeutic interventions.

Project description:ObjectiveThe objective was to develop a multiparametric CT algorithm to stage liver fibrosis in patients with chronic hepatitis C virus (HCV) infection.Materials and methodsAbdominal CT and laboratory measures in 469 patients with HCV (340 men and 129 women; mean age, 50.1 years) were compared against the histopathologic Metavir fibrosis reference standard (F0, n = 49 patients; F1, n = 69 patients; F2, n = 102 patients; F3, n = 76 patients; F4, n = 173 patients). From the initial candidate pool, nine CT and two laboratory measures were included in the final assessment (CT-based features: hepatosplenic volumetrics, texture features, liver surface nodularity [LSN] score, and linear CT measurements; laboratory-based measures: Fibrosis-4 [FIB-4] score and aspartate transaminase-to-platelets ratio index [APRI]). Univariate logistic regression and multivariate logistic regression were performed with ROC analysis, proportional odds modeling, and probabilities.ResultsROC AUC values for the model combining all 11 parameters for discriminating significant fibrosis (≥ F2), advanced fibrosis (≥ F3), and cirrhosis (F4) were 0.928, 0.956, and 0.972, respectively. For all nine CT-based parameters, these values were 0.905, 0.936, and 0.972, respectively. Using more simplified panels of two, three, or four parameters yielded good diagnostic performance; for example, a two-parameter model combining only LSN score with FIB-4 score had ROC AUC values of 0.886, 0.915, and 0.932, for significant fibrosis, advanced fibrosis, and cirrhosis. The LSN score performed best in the univariate analysis.ConclusionMultiparametric CT assessment of HCV-related liver fibrosis further improves performance over the performance of individual parameters. An abbreviated panel of LSN score and FIB-4 score approached the diagnostic performance of more exhaustive panels. Results of the abbreviated panel compare favorably with elastography, but this approach has the advantage of retrospective assessment using preexisting data without planning.

Dataset Information

In-vivo lung fibrosis staging in a bleomycin-mouse model: a new micro-CT guided densitometric approach.

Publications

In-vivo lung fibrosis staging in a bleomycin-mouse model: a new micro-CT guided densitometric approach.

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