Longitudinal micro-CT provides biomarkers of lung disease that can be used to assess the effect of therapy in preclinical mouse models, and reveal compensatory changes in lung volume.
Longitudinal micro-CT provides biomarkers of lung disease that can be used to assess the effect of therapy in preclinical mouse models, and reveal compensatory changes in lung volume.
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DOI：
10.1242/dmm.020321
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发表时间：
2016-01
影响因子：
4.3
通讯作者：
Lories RJ
中科院分区：
文献类型：
--
作者：
Vande Velde G;Poelmans J;De Langhe E;Hillen A;Vanoirbeek J;Himmelreich U;Lories RJ
在活体肺微计算机断层扫描(Micro-CT)在肺部研究中越来越受到欢迎，因为它提供了动态疾病过程的纵向信息，在这个领域，对实验性疾病模型的体外评估仍然是金标准。为了优化肺部疾病进展和治疗的定量监测，我们评估了四种不同的Micro-CT衍生生物标志物[充气肺体积、肺组织(包括病变)体积、总肺体积和平均肺密度]的纵向变化，描述了正常发育、肺部感染、炎症、纤维化和治疗。自由呼吸小鼠在诱导肺部疾病(博莱霉素性纤维化、侵袭性肺曲霉菌病、肺隐球菌病)和治疗(伊马替尼)之前和之后重复进行Micro-CT检查。对四种肺生物标志物进行量化。在最后一个时间点后，我们进行肺功能测试，并分离肺进行组织学检查。在对成年健康小鼠肺的纵向随访中，没有一个生物标志物保持稳定，这意味着在干预时，生物标志物应该与年龄匹配的对照组进行比较。早期炎症和进行性纤维化导致总肺体积显著增加，这影响了对充气肺体积、组织体积和平均肺密度测量的解释。在治疗纤维化肺疾病时，充气肺容量和功能的改善并不伴随着增加的总肺容量的正常化。在快速和缓慢进展的肺部感染模型中也存在明显增大的肺。这些数据表明，总肺容量的变化可能在一定程度上反映了在小鼠疾病进展过程中发生的代偿机制。我们的发现强调了除了充气肺或病变体积之外，量化总肺体积的重要性，以准确地记录肺部疾病小鼠模型的生长和潜在的代偿机制，以便全面描述和理解肺部疾病发生、发展和治疗过程中的动态过程。这对于将临床前研究的治疗评估结果转化为人类患者是高度相关的。摘要：在评价小鼠肺部疾病及其治疗的模型中，不仅要量化充气肺体积或病变体积，而且要量化来自Micro-CT的总肺体积，以记录生长和潜在的代偿机制。
In vivo lung micro-computed tomography (micro-CT) is being increasingly embraced in pulmonary research because it provides longitudinal information on dynamic disease processes in a field in which ex vivo assessment of experimental disease models is still the gold standard. To optimize the quantitative monitoring of progression and therapy of lung diseases, we evaluated longitudinal changes in four different micro-CT-derived biomarkers [aerated lung volume, lung tissue (including lesions) volume, total lung volume and mean lung density], describing normal development, lung infections, inflammation, fibrosis and therapy. Free-breathing mice underwent micro-CT before and repeatedly after induction of lung disease (bleomycin-induced fibrosis, invasive pulmonary aspergillosis, pulmonary cryptococcosis) and therapy (imatinib). The four lung biomarkers were quantified. After the last time point, we performed pulmonary function tests and isolated the lungs for histology. None of the biomarkers remained stable during longitudinal follow-up of adult healthy mouse lungs, implying that biomarkers should be compared with age-matched controls upon intervention. Early inflammation and progressive fibrosis led to a substantial increase in total lung volume, which affects the interpretation of aerated lung volume, tissue volume and mean lung density measures. Upon treatment of fibrotic lung disease, the improvement in aerated lung volume and function was not accompanied by a normalization of the increased total lung volume. Significantly enlarged lungs were also present in models of rapidly and slowly progressing lung infections. The data suggest that total lung volume changes could partly reflect a compensatory mechanism that occurs during disease progression in mice. Our findings underscore the importance of quantifying total lung volume in addition to aerated lung or lesion volumes to accurately document growth and potential compensatory mechanisms in mouse models of lung disease, in order to fully describe and understand dynamic processes during lung disease onset, progression and therapy. This is highly relevant for the translation of therapy evaluation results from preclinical studies to human patients. Summary: Quantifying not only aerated lung volume or lesion volumes but also the total lung volume from micro-CT is essential to document growth as well as potential compensatory mechanisms in the evaluation of mouse models of lung diseases and their therapy.