Longitudinal Micro‑CT Derived Biomarkers in Silicosis Fibrosis Model

Pulmonary Fibrosis (PF) is a type of interstitial lung disease with a poor prognosis and response to current therapies. During the progress of this disease, the build-up of fibrotic tissue leads to an overall rigidity of lung architecture, leading to a gradual decline in lung function.

Despite a wealth of experimental findings on pathogenic mechanisms and promising therapeutic targets, there are only a few drugs currently available to slow down the progression of PF and not halt nor reverse the disease. This translational gap in the PF field from bench to bedside has been slowly converging. This disparity is due to several factors, such as the limitations in current PF animal models being able to exactly mimic the human PF disease in terms of screening techniques and the evolution of the disease.

A recent publication by Dekoster, K., et al, (2020) in Nature Scientific Reports sheds light on the importance of using longitudinal biomarkers in pre-clinical fibrosis models to identify early critical windows for therapeutic intervention. In this study, researchers used micro-computer-tomography to monitor the progression of experimental silica-induced PF, which were then cross-validated by end-point lung mechanics measurements, inflammatory evaluations, and histopathological analysis at each time point. Researchers chose a silica-induced model of PF as it serves as non-resolving fibrosis similar to a human PF and is more persistent with a longer disease window to test progression and therapeutics when compared to the classic Bleomycin model.

In this study, two main parameters derived from their Micro-CT Scans were; the non-aerated lung volume (a biomarker for the degree of pathology) and the aerated lung volume (a biomarker for lung function). Overall, both the aerated and non-aerated lung volume was significantly increased in the silica-induced model when compared to the saline controls. The flexiVent system was used in conjunction to characterize complete lung function at every target endpoint, to cross-validate microCT findings. Results show that tissue hysteresivity correlated nicely with the total Lung Volume, and the clinically translatable measurements of flow limitation correlated with non-aerated volume. Additionally, inspiratory capacity correlated with the aerated lung volume. Interestingly, certain ex vivo inflammatory and fibrotic readouts, such as protein concentrations in BAL and serum, along with hydroxyproline, correlated with the non-aerated lung volume.

This study demonstrates that in vivo longitudinal μCT-derived biomarkers allow for validated identification and quantification of disease progression in a longitudinal approach to silica-induced PF models.