Summary

Drug-induced interstitial lung disease (ILD) is crucial to detect early to achieve the best treatment outcome. Optimally, non-invasive imaging biomarkers can be used for early detection of disease progression and treatment follow-up. Therefore, reliable in vivo models are warranted in new imaging biomarker development to accelerate better-targeted treatment options. Single-dose bleomycin models have, for a long time, served as a reference model in fibrosis and lung injury research. The publication aims to use a clinically more relevant animal model by systemic exposure to bleomycin and assessing disease progression over time by combined magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging.

Methods

At each scan session the injected radiotracer was allowed to circulate systemically for about 1 h (partially during the MRI acquisition) before the PET imaging was initiated. Directly after MRI acquisition, an initial overview scan (scout-view scan) was performed before PET/CT imaging (the acquisition was about 2 min) to obtain the optimal position of the animal. After processing the scout-view image, the optimal FOV was adjusted to ensure coverage of the entire lungs, followed by a CT scan of 10 min acquisition time, and immediately thereafter PET imaging was done. The PET scan acquisition time was 20 min, initiated 1 h (±5 min) after tracer injection.

Results from nanoScan^® PET/CT

PET/CT acquisitions were performed on a Mediso imaging system (nanoScan^® PET/CT, Mediso, Hungary) for the overall monitoring of increased cell and tissue metabolism by employing the [¹⁸F]FDG tracer. The PET data was reconstructed by applying standard protocol of Maximum Likelihood Estimation Method (MLEM post-reconstruction protocol) using the Nucline v2.01 nanoScan software. The signal from the PET images was divided by the decay-corrected injected dose to each animal to calculate the fractional uptake, i.e., total activity uptake per mm³ and the total uptake in the whole lung, which is referred to as tracer uptake.

• Due to the vast capillary bed, the injury caused by bleomycin in this model emanates from the vascular side and progresses from the distal into the central parts of the lung rather than originating from the central airways as in the traditional intratracheal bleomycin model. This was not only evident by the histological assessments throughout the study but became visible by using live imaging.
• PET imaging showed the increased [¹⁸F]FDG uptake in the lungs that could be an indication of the continuous disease activity in a non-resolving and progressive fibrosis model, both during the dosing period and during the resting period (see Figure 7A). This is different from what has been shown previously in the acute bleomycin model, with intratracheal administration in rats or mice.

Figure 7A [¹⁸F]FDG imaging at the last dosing week compared to the last resting week, shown at two separate time points. PET images were co-registered and overlaid with MRI for anatomical registration and lesion identification and presented for visualization, only showing PET-signal within the lung-ROI.

• [¹⁸F]FDG proved to be a valuable biomarker for lung injury in general, both during inflammation and fibrogenesis. This tracer can be used to evaluate ongoing metabolic processes, regardless of the type of disease profile, consequently serves as an effective biomarker for detecting active disease progression.
• Comparing the measures between MRI and PET, a positive correlation was observed between the total [¹⁸F]FDG uptake and the lesion volume assessed by MRI in the whole lung region.

Conclusion

Non-invasive imaging displayed progressing lesions in the lungs of bleomycin-exposed mice, using two distinct MRI sequences and [¹⁸F]FDG-PET. With observed fibrosis progression emanating from distal lung areas, dilation of the central airways was evident. Taken together, this chronic bleomycin-exposure model is translationally more relevant for studying lung injury in ILD and particularly in the context of DIILD.

Original link: Frontiers in Medicine