Longitudinal Micro-Computed Tomography Detects Onset and Progression of Pulmonary Fibrosis in Conditional Nedd4-2 Deficient Mice

ObjectivesIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease which is usually diagnosed late in advanced stages. Little is known about the subclinical development of IPF. We previously generated a mouse model with conditional Nedd4-2 deficiency (Nedd4-2-/-) that develops IPF-like lung disease. The aim of this study was to characterize the onset and progression of IPF-like lung disease in conditional Nedd4-2-/- mice by longitudinal micro- computed tomography (CT). MethodsIn vivo micro-CT was performed longitudinally in control and conditional Nedd4- 2-/- mice at 1, 2, 3, 4 and 5 months after doxycycline induction. Further, terminal in vivo micro-CT followed by pulmonary function testing and post mortem micro-CT was performed in age-matched mice. Micro-CT images were evaluated for pulmonary fibrosis using an adapted fibrosis scoring system. ResultsMicro-CT is sensitive to detect onset and progression of pulmonary fibrosis in vivo and to quantify distinct radiological IPF-like features along disease development in conditional Nedd4-2-/- mice. Nonspecific interstitial alterations were detected from 3 months, whereas key features such as honeycombing-like lesions were detected from 4 months onwards. Pulmonary function inversely correlated with in vivo (r=-0.725) and post mortem (r=-0.535) micro-CT fibrosis scores. ConclusionLongitudinal micro-CT enables in vivo monitoring of onset and progression and detects radiologic key features of IPF-like lung disease in conditional Nedd4-2-/- mice. Our data support micro-CT as sensitive quantitative endpoint for preclinical evaluation of novel antifibrotic strategies. NEW & NOTEWORTHYIPF diagnosis, particularly in early stages, remains challenging. In this study micro-CT is used in conditional Nedd4-2-/- mice to closely monitor the onset and progression of IPF-like lung disease. This allowed us to track for the first time how nonspecific lung lesions develop into key IPF-like features. This approach offers a non-invasive method to monitor pulmonary fibrosis in vivo, providing a quantitative endpoint for preclinical evaluation of novel antifibrotic strategies.