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- Boswinkel, Milou, et al.
(författare)
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Utilizing MRI, [18F]FDG-PET and [89Zr]Zr-DFO-28H1 FAP-PET tracer to assess inflammation and fibrogenesis in a reproducible lung injury rat model : a multimodal imaging study
- 2023
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Ingår i: Frontiers in Nuclear Medicine. - 2673-8880. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Accurate imaging biomarkers that indicate disease progression at an early stage are highly important to enable timely mitigation of symptoms in progressive lung disease. In this context, reproducible experimental models and readouts are key. Here, we aim to show reproducibility of a lung injury rat model, by inducing disease and assessing disease progression by multi-modal non-invasive imaging techniques at two different research sites. Furthermore, we evaluated the potential of fibroblast activating protein (FAP) as an imaging biomarker in the early stage of lung fibrosis. Methods: An initial lung injury rat model was set up at one research site (Lund University, Lund, Sweden) and repeated at a second site (Radboudumc, Nijmegen, The Netherlands). To induce lung injury, Sprague-Dawley rats received intratracheal instillation of bleomycin as one single dose (1,000 iU in 200 µL) or saline as control. Thereafter, longitudinal images were acquired to track inflammation in the lungs, at 1 and 2 weeks after the bleomycin challenge by magnetic resonance imaging (MRI) and [18F]FDG-PET. After the final [18F]FDG-PET scan, rats received an intravenous tracer [89Zr]Zr-DFO-28H1 (anti-FAP antibody) and were imaged at day 15, to track fibrogenesis. Upon termination, bronchoalveolar lavage (BAL) was performed to assess cell and protein concentration. Subsequently, the biodistribution of [89Zr]Zr-DFO-28H1 was measured ex vivo and the spatial distribution in lung tissue was studied by autoradiography. Lung sections were stained, and fibrosis assessed using the modified Ashcroft score. Results: Bleomycin-challenged rats showed body weight loss and increased numbers of immune cells and protein concentrations after BAL compared with control animals. The initiation and progression of the disease were reproduced at both research sites. Lung lesions in bleomycin-exposed rats were visualized by MRI and confirmed by histology. [18F]FDG uptake was higher in the lungs of bleomycin-challenged rats compared with the controls, similar to that observed in the Lund study. [89Zr]Zr-DFO-28H1 tracer uptake in the lung was increased in bleomycin-challenged rats compared with control rats (p = 0.03). Conclusion: Here, we demonstrate a reproducible lung injury model and monitored disease progression using conventional imaging biomarkers MRI and [18F]FDG-PET. Furthermore, we showed the first proof-of-concept of FAP imaging. This reproducible and robust animal model and imaging experimental set-up allows for future research on new therapeutics or biomarkers in lung disease.
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| 2. |
- Waterton, John C., et al.
(författare)
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Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems
- 2019
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Ingår i: Magnetic Resonance Imaging. - : Elsevier BV. - 1873-5894 .- 0730-725X. ; 59, s. 121-129
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R 1 , but evidence for between-site reproducibility of R 1 in small-animal MRI is lacking. Objective: To assess R 1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. Methods: R 1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1–13 days. R 1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured. Results: CoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R 1 -based MR biomarkers were found to be quite sensitive even to such small errors in R 1 , notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni 2+ in 2% agarose varied between 0.66 s −1 mM −1 at 3 T and 0.94 s −1 mM −1 at 11.7T. Interpretation: While several factors affect the reproducibility of R 1 -based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R 1 -reproducibility.
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