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Publication

Novel imaging-derived morphological and functional biomarkers of lung disease in mouse models

Book - Dissertation

Pulmonary fibrosis is the replacement of healthy tissue by an excessive deposition of extracellular matrix components leading to an irreversible destruction of the lung architecture. It is a devastating condition resulting in a decreased lung compliance, disrupted gas exchange and respiratory failure. Currently, there are two therapeutics on the market that slow down the progression of pulmonary fibrosis. Regardless many efforts made in the past, there is still no curative treatment available. As such, pulmonary fibrosis remains a life-threatening condition. Therefore, in this thesis, in order to improve state-of-the-art approaches in preclinical pulmonary fibrosis research towards new therapies and targets, we aimed to (1) implement safe and repeated low-dose µCT, (2) optimize an image-compatible, stable and non-resolving pulmonary fibrosis mouse model, (3) evaluate the relevance of µCT in preclinical therapy studies and (4) extract lung function biomarkers from longitudinal µCT data of free-breathing mice with different lung pathologies. By weekly scanning murine models of lung metastasis, inflammation and fibrosis with µCT and comparing 5-times weekly scanned animals with unscanned controls, we found no influence of µCT on lung metastasis load nor on healthy mice. We saw a disease-independent reduction in circulating blood platelets and lymphocytes when using a 4D µCT protocol, which we could eliminate by altering our protocol to 3D µCT thereby reducing the delivered dose by two-thirds. We established that consecutive scanning with µCT was safe to use in different murine models. Next, we established a silicosis mouse model of pulmonary fibrosis by oropharyngeal instillation of silica particles in mice. After instillation, these animals were monitored by in vivo µCT. Our µCT-derived morphological biomarkers were able to monitor the early onset of inflammatory and long-term non-resolving pulmonary fibrosis in this silicosis mouse model. Additionally, we used a commercially available therapeutic, Nintedanib, to validate µCT for preclinical therapy testing. Nintedanib treatment slightly decreased the non-aerated lung volume in both treatment regimes, while it increased the aerated and total lung volume as assessed by µCT. Although Nintedanib only showed a subtle treatment effect and the severity of the mouse model was only minor, there was a good agreement between in vivo µCT biomarkers and ex vivo readouts (e.g. flexiVent, histology and inflammatory markers). At last, we explored novel functional biomarkers derived from an in vivo 4D µCT scan: the tidal volume and centre of tidal volume. These biomarkers allow non-invasive follow-up of lung function in mice and are complementary to other invasive endpoint methods. This last part further emphasized the need of µCT to evaluate preclinical lung disease models. To conclude, with this thesis, we provided substantial evidence to implement µCT to the routine workflow for preclinical lung fibrosis research, thereby improving preclinical assessment of therapeutics and solving the gap between bench and bedside translatability.
Publication year:2022
Accessibility:Open