Longitudinal Micro-Computed Tomography Detects Onset and Progression of Pulmonary Fibrosis in ConditionalNedd4-2Deficient Mice

Abstract

ABSTRACTObjectivesIdiopathic 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 conditionalNedd4-2deficiency (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 conditionalNedd4-2−/−mice by longitudinal micro- computed tomography (CT).MethodsIn vivomicro-CT was performed longitudinally in control and conditionalNedd4- 2−/−mice at 1, 2, 3, 4 and 5 months after doxycycline induction. Further, terminalin vivomicro-CT followed by pulmonary function testing andpost mortemmicro-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 fibrosisin vivoand to quantify distinct radiological IPF-like features along disease development in conditionalNedd4-2−/−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 within vivo(r=-0.725) andpost mortem(r=-0.535) micro-CT fibrosis scores.ConclusionLongitudinal micro-CT enablesin vivomonitoring of onset and progression and detects radiologic key features of IPF-like lung disease in conditionalNedd4-2−/−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 conditionalNedd4-2−/−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 fibrosisin vivo, providing a quantitative endpoint for preclinical evaluation of novel antifibrotic strategies.