Journal article
Ferret models of alpha-1 antitrypsin deficiency develop lung and liver disease
JCI insight, Vol.7(5), e143004
03/08/2022
DOI: 10.1172/jci.insight.143004
PMCID: PMC8983124
PMID: 35104244
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.
Details
- Title: Subtitle
- Ferret models of alpha-1 antitrypsin deficiency develop lung and liver disease
- Creators
- Nan He - University of IowaXiaoming Liu - University of IowaAmber R Vegter - University of IowaT Idil A Evans - University of IowaJaimie S Gray - University of IowaJunfeng Guo - University of IowaShashanna R Moll - University of IowaLydia J Guo - University of IowaMeihui Luo - University of IowaNingxia Ma - University of IowaXingshen Sun - University of IowaBo Liang - University of IowaZiying Yan - University of IowaZehua Feng - University of IowaLisi Qi - University of IowaArnav S Joshi - University of IowaWeam Shahin - University of IowaYaling Yi - University of IowaKatherine N Gibson-Corley - University of IowaEric A Hoffman - University of IowaKai Wang - University of IowaChristian Mueller - Department of Pediatrics, University of Massachusetts Medical Center, Worcester, United States of America.John F Engelhardt - University of IowaBradley H Rosen - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.7(5), e143004
- DOI
- 10.1172/jci.insight.143004
- PMID
- 35104244
- PMCID
- PMC8983124
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R24 HL123482, 75N92019C00010; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, award: Carver Chair in Molecular Medicine; DOI: 10.13039/100000002, name: National Institutes of Health, award: T32 HL007638, KL2 TR002536; DOI: 10.13039/100001448, name: Alpha-1 Foundation, award: Research grant
- Language
- English
- Date published
- 03/08/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Anatomy and Cell Biology; Biostatistics; Radiation Oncology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984230043202771
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