Monitoring the response to Nintedanib treatment in a mouse model of lung fibrosis using longitudinal X-ray based lung function measurement


Khan A, Markus AM, Svetlove A, Hülsmann S, Alves F, Dullin C


Research Square


Research Square, 12 April 2023, preprint.


Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive, incurable, and debilitating fibrotic disease. Nintedanib – an oral tyrosine kinase inhibitor – significantly slows the IPF progression. However, reliable diagnostic tools for functional assessment of IPF at early stages are essentially lacking at both clinical and pre-clinical level.
Methods: In this study, we used a correlative set-up that combines X-ray based lung function (XLF) with microCT and whole body plethysmography (WBP) for a comprehensive functional and structural evaluation of lung fibrosis (LF) as well as for monitoring response to orally administered Nintedanib in the mouse model of bleomycin induced LF.
Results: The decline in lung function as early as one week after intratracheal bleomycin instillation was reliably detected by XLF, revealing the lowest decay rate in the LF mice compared to healthy ones. Simultaneously performed microCT and WBP measurements corroborated XLF findings by exhibiting reduced lung volume VinspµCT and tidal volume TVWBP at inspiration. In LF mice XLF also revealed profound improvement in lung function one week after Nintedanib treatment. This positive response to Nintedanib therapy was further substantiated by microCT and WBP measurements which also showed significantly improved VinspµCT and TVWBP in the Nintedanib treated mice.
Conclusion: By comparing the XLF data to structural features assessing the extent of fibrosis obtained by ex-vivo high-resolution synchrotron radiation-based imaging of lungs and classical histology we demonstrate that: i) a simple low dose x-ray measurement like XLF is sensitive enough to pick up treatment response, ii) Nintedanib treatment successfully improved lung function in a bleomycin induced LF mouse model and iii) the differences between the fully restored lung function and the partially reduced fiberotic burden compared to healthy and untreated mice. The presented analysis pipeline underlines the importance of a combined functional and anatomical readout to reliably measure treatment response and could easily be adapted to other preclinical lung disease models.