Longitudinal in vivo microcomputed tomography of mouse lungs: No evidence for radiotoxicity

摘要

Even when in some cases the cause is obvious (e.g., smoking, etc.), many aspects of the pathophys-iology of lung diseases remain poorly understood. To understand etiology, prevent a disease from fully developing or progressing, and find targets for effective treatment, additional research is essential. Research to unravel disease processes in the lung and to develop new therapeutic strategies in a preclin-ical setting heavily relies on small animal models (4, 6, 24, 25, 30, 38). The resulting lung pathology is routinely quantified by labor-intensive ex vivo histological assessments, currently the gold standard for evaluation of pathology and its therapy in these animals. Although histological techniques will always remain essential to unravel pathogenesis at a molecular and cellular level, they lack the ability to provide dynamic information on disease progression and potential therapeutic effects. Because the time of onset, course of disease progression, and potential response to therapy in (transgenic) rodent models may be unpredictable and/or show substantial interindividual variation (23, 25), noninvasive techniques are indispensable to dynamically monitor disease development and progression and to establish the kinetics of pathogenic events or treatment effects for each animal individually. Because noninvasive pulmonary function measurements have limitations regarding sensitivity, specificity, and available readout (16, 19, 41), several imaging tools for the evaluation of lung disease are currently being explored (15). Nonetheless, imaging techniques combining sensitivity with good temporal and spatial resolution in vivo are limited. Based on its excellent air-tissue contrast, in vivo microcomputed tomography (micro-CT) has proven to be an efficient and safe noninvasive method to provide dynamic quantitative information on lung emphysema and fibrosis progression, including therapy response over a time span of several weeks in mice, thereby having experimental, ethical, statistical, and economic advantages compared with the standard histological approach (9). However, before extending lung micro-CT scanning protocols to animal models that require more frequent scanning and/or scanning over longer periods of time (e.g., in transgenic mouse models with slow and/or unpredictable disease onset), radiotoxicity issues that could interfere with the micro-CT readout for the lung are often raised as a possible concern and must be considered. Because lungs are particularly sensitive to higher (cumulative)