Department of Anatomy and Cell Biology.
Department of Radiology.
JCI Insight. 2022 Mar 8;7(5):e143004. doi: 10.1172/jci.insight.143004.
Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause and risk factor for chronic obstructive pulmonary disease, but the field lacks a large-animal model that allows for longitudinal assessment of pulmonary function. We hypothesized that ferrets would model human AATD-related lung and hepatic disease. AAT-knockout (AAT-KO) and PiZZ (E342K, the most common mutation in humans) ferrets were generated and compared with matched controls using custom-designed flexiVent modules to perform pulmonary function tests, quantitative computed tomography (QCT), bronchoalveolar lavage (BAL) proteomics, and alveolar morphometry. Complete loss of AAT (AAT-KO) led to increased pulmonary compliance and expiratory airflow limitation, consistent with obstructive lung disease. QCT and morphometry confirmed emphysema and airspace enlargement, respectively. Pathway analysis of BAL proteomics data revealed inflammatory lung disease and impaired cellular migration. The PiZ mutation resulted in altered AAT protein folding in the liver, hepatic injury, and reduced plasma concentrations of AAT, and PiZZ ferrets developed obstructive lung disease. In summary, AAT-KO and PiZZ ferrets model the progressive obstructive pulmonary disease seen in AAT-deficient patients and may serve as a platform for preclinical testing of therapeutics including gene therapy.
α-1 抗胰蛋白酶缺乏症（AATD）是慢性阻塞性肺疾病最常见的遗传原因和危险因素，但该领域缺乏一种大型动物模型，无法对肺功能进行纵向评估。我们假设雪貂可以模拟人类 AATD 相关的肺和肝疾病。使用定制的 flexiVent 模块生成 AAT 敲除（AAT-KO）和 PiZZ（E342K，人类最常见的突变）雪貂，并与匹配的对照进行比较，以进行肺功能测试、定量计算机断层扫描（QCT）、支气管肺泡灌洗（BAL）蛋白质组学和肺泡形态计量学分析。AAT 的完全缺失（AAT-KO）导致肺顺应性增加和呼气气流受限，与阻塞性肺疾病一致。QCT 和形态计量学分别证实了肺气肿和气腔扩大。BAL 蛋白质组学数据分析的途径分析显示出炎症性肺病和细胞迁移受损。PiZ 突变导致肝脏中 AAT 蛋白折叠改变、肝损伤和 AAT 血浆浓度降低，PiZZ 雪貂发生阻塞性肺疾病。总之，AAT-KO 和 PiZZ 雪貂可模拟 AAT 缺乏患者中所见的进行性阻塞性肺疾病，并且可以作为包括基因治疗在内的治疗方法的临床前测试平台。
