Longitudinal microcomputed tomography detects onset and progression of pulmonary fibrosis in conditional <i>Nedd4-2</i> deficient mice

Idiopathic 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 <i>Nedd4-2</i> deficiency (<i>Nedd4-2^-/-</i>) 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 <i>Nedd4-2^-/-</i> mice by longitudinal micro-computed tomography (CT). In vivo micro-CT was performed longitudinally in control and conditional <i>Nedd4-2^-/-</i> mice at 1, 2, 3, 4, and 5 mo after doxycycline induction. Furthermore, 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. Histological assessment of lung collagen content was conducted as well. Micro-CT is sensitive to detect the onset and progression of pulmonary fibrosis in vivo and to quantify distinct radiological IPF-like features along disease development in conditional <i>Nedd4-2^-/-</i> mice. Nonspecific interstitial alterations were detected from 3 mo, whereas key features such as honeycombing-like lesions were detected from 4 mo onward. Pulmonary function correlated well with in vivo (<i>r</i> = -0.738) and post mortem (<i>r</i> = -0.633) micro-CT fibrosis scores and collagen content. Longitudinal micro-CT enables in vivo monitoring of the onset and progression and detects radiological key features of IPF-like lung disease in conditional <i>Nedd4-2^-/-</i> mice. Our data support micro-CT as a sensitive quantitative endpoint for the preclinical evaluation of novel antifibrotic strategies.<b>NEW & NOTEWORTHY</b> IPF diagnosis, particularly in early stages, remains challenging. In this study, micro-CT is used in conditional <i>Nedd4-2^-/-</i> mice to closely monitor the onset and progression of progressive pulmonary fibrosis in vivo. Together with high-resolution post mortem micro-CT, this allowed us to track how nonspecific lung lesions develop into key IPF-like features. This approach offers a noninvasive method to monitor pulmonary fibrosis, providing a quantitative endpoint for the preclinical evaluation of novel antifibrotic strategies.