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

Science and Research

OBJECTIVES: 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 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). METHODS: In 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. Histological assessment of lung collagen content was conducted as well. RESULTS: Micro-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 correlated well with in vivo (r=-0.738) and post mortem (r=-0.633) micro-CT fibrosis scores and collagen content. CONCLUSION: Longitudinal 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.