Cleveland Zackary I, Zhou Yu M, Akinyi Teckla G, Dunn R Scott, Davidson Cynthia R, Guo Jinbang, Woods Jason C, Hardie William D
Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Am J Physiol Lung Cell Mol Physiol. 2017 Apr 1;312(4):L488-L499. doi: 10.1152/ajplung.00458.2016. Epub 2017 Jan 27.
Pulmonary fibrosis contributes to morbidity and mortality in a range of diseases, and there are no approved therapies for reversing its progression. To understand the mechanisms underlying pulmonary fibrosis and assess potential therapies, mouse models are central to basic and translational research. Unfortunately, metrics commonly used to assess murine pulmonary fibrosis require animals to be grouped and euthanized, increasing experimental difficulty and cost. We examined the ability of magnetic resonance imaging (MRI) to noninvasively assess lung fibrosis progression and resolution in a doxycycline (Dox) regulatable, transgenic mouse model that overexpresses transforming growth factor-α (TGF-α) under control of a lung-epithelial-specific promoter. During 7 wk of Dox treatment, fibrotic lesions were readily observed as high-signal tissue. Mean weighted signal and percent signal volume were found to be the most robust MRI-derived measures of fibrosis, and these metrics correlated significantly with pleural thickness, histology scores, and hydroxyproline content ( = 0.75-0.89). When applied longitudinally, percent high signal volume increased by 1.5% wk ( < 0.001) and mean weighted signal increased at a rate of 0.0065 wk ( = 0.0062). Following Dox treatment, lesions partially resolved, with percent high signal volume decreasing by -3.2% wk ( = 0.0034) and weighted mean signal decreasing at -0.015 wk ( = 0.0028). Additionally, longitudinal MRI revealed dynamic remodeling in a subset of lesions, a previously unobserved behavior in this model. These results demonstrate MRI can noninvasively assess experimental lung fibrosis progression and resolution and provide unique insights into its pathobiology.
肺纤维化在一系列疾病中会导致发病和死亡，目前尚无获批的疗法来逆转其进展。为了解肺纤维化的潜在机制并评估潜在疗法，小鼠模型是基础研究和转化研究的核心。不幸的是，常用于评估小鼠肺纤维化的指标需要将动物分组并实施安乐死，这增加了实验难度和成本。我们在一种强力霉素（Dox）可调控的转基因小鼠模型中，研究了磁共振成像（MRI）非侵入性评估肺纤维化进展和消退的能力，该模型在肺上皮特异性启动子的控制下过表达转化生长因子-α（TGF-α）。在Dox治疗的7周内，纤维化病变很容易被观察为高信号组织。发现平均加权信号和信号体积百分比是MRI衍生的最可靠的纤维化测量指标，这些指标与胸膜厚度、组织学评分和羟脯氨酸含量显著相关（= 0.75 - 0.89）。纵向应用时，高信号体积百分比每周增加1.5%（< 0.001），平均加权信号以每周0.0065的速率增加（= 0.0062）。Dox治疗后，病变部分消退，高信号体积百分比每周下降-3.2%（= 0.0034），加权平均信号每周下降-0.015（= 0.0028）。此外，纵向MRI显示在一部分病变中存在动态重塑，这是该模型中以前未观察到的行为。这些结果表明MRI可以非侵入性评估实验性肺纤维化的进展和消退，并为其病理生物学提供独特的见解。
