Ferret models of alpha-1 antitrypsin deficiency develop lung and liver disease.

Nan He,Junfeng Guo,Weam Shahin,Yaling Yi,Shashanna R Moll,Jaimie S Gray,Kai Wang,Ziying Yan,Meihui Luo,John F Engelhardt,Christian Mueller,Bradley H Rosen,Eric A Hoffman,Ningxia Ma,Xingshen Sun,Bo Liang,Xiaoming Liu,Lisi Qi,Zhanlian Feng ,Arnav S Joshi ,Katherine N Gibson‐Corley ,T Idil Apak Evans ,Amber R Vegter ,Lydia J Guo

doi:10.1172/jci.insight.143004

Nan He, Junfeng Guo + Show 22 more

Open Access

https://doi.org/10.1172/jci.insight.143004

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Abstract

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.

Highlights

Alpha-1 antitrypsin deficiency (AATD) is the most common genetic risk factor for developing emphysema, a form of chronic obstructive pulmonary disease (COPD)
Because other proteins can act as antiproteases [9, 28], we measured the capacity of alpha-1 antitrypsin (AAT)-KO and control plasma to inhibit activated neutrophil elastase (NE)
These findings confirm that AAT is required to prevent spontaneous emphysema in the ferret, which mirror and expand upon the results reported in the Serpina1a-e knockout mouse [20]

Summary

Introduction

Alpha-1 antitrypsin deficiency (AATD) is the most common genetic risk factor for developing emphysema, a form of chronic obstructive pulmonary disease (COPD). (SERPINA1) gene, which result in low circulating levels of alpha-1 antitrypsin (AAT), a protease inhibitor that protects tissues from excessive protease activity [3,4,5]. AAT counterbalances the activities of proteases such as neutrophil elastase (NE), cathepsin G, proteinase-3, and matrix metalloproteinases, which contribute to destruction of the distal airways and alveolar walls [9, 10]. SERPINA1 mutations that completely abolish AAT protein expression have been identified [11, 12], and this absence of AAT leads to pulmonary emphysema and chronic bronchitis without liver disease [10, 13]. AATD is more commonly caused by a point mutation (Z-allele) that leads to protein aggregation within hepatocytes, hepatotoxicity, and reduced AAT plasma levels [14,15,16]. Humans homozygous for the Z-allele (PiZZ) are highly susceptible to excessive protease-mediated damage related to environmental exposures and inflammatory stimuli to the lung, exposure to tobacco smoke [5]

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