Dataset Information

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

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.

SUBMITTER: He N

PROVIDER: S-EPMC8983124 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

He Nan N Liu Xiaoming X Vegter Amber R AR Evans T Idil A TIA Gray Jaimie S JS Guo Junfeng J Moll Shashanna R SR Guo Lydia J LJ Luo Meihui M Ma Ningxia N Sun Xingshen X Liang Bo B Yan Ziying Z Feng Zehua Z Qi Lisi L Joshi Arnav S AS Shahin Weam W Yi Yaling Y Gibson-Corley Katherine N KN Hoffman Eric A EA Wang Kai K Mueller Christian C Engelhardt John F JF Rosen Bradley H BH

JCI insight 20220308 5

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 perf ...[more]

PMID: 35104244

Similar Datasets

Project description:BackgroundAlpha-1 antitrypsin deficiency is an inherited disorder that can cause chronic obstructive pulmonary disease (COPD). People who smoke are more seriously affected and have a greater risk of dying from the disease. Therefore, the primary treatment is to help people give up smoking. There are now also preparations available that contain alpha-1 antitrypsin, but it is uncertain what their clinical effect is.ObjectivesTo review the benefits and harms of augmentation therapy with intravenous alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed and ClinicalTrials.gov to 25 March 2016.Selection criteriaWe included randomised trials of augmentation therapy with alpha-1 antitrypsin compared with placebo or no treatment.Data collection and analysisThe two review authors independently selected trials, extracted outcome data and assessed the risk of bias.Main resultsWe included three trials (283 participants in the analyses) that ran for two to three years. All participants were ex- or never-smokers and had genetic variants that carried a high risk of developing COPD. Only one trial reported mortality data (one person of 93 died in the treatment group and three of 87 died in the placebo group). There was no information on harms in the oldest trial. Another trial reported serious adverse events in 10 participants in the treatment group and 18 participants in the placebo group. In the most recent trial, serious adverse events occurred in 28 participants in each group. None of the trials reported mean number of lung infections or hospital admissions. In the two trials that reported exacerbations, there were more exacerbations in the treatment group than in the placebo group, but the results of both trials included the possibility of no difference. Quality of life was similar in the two groups. Forced expiratory volume in one second (FEV1) deteriorated more in participants in the treatment group than in the placebo group but the confidence interval (CI) included no difference (standardised mean difference -0.19, 95% CI -0.42 to 0.05; P = 0.12). For carbon monoxide diffusion, the difference was -0.11 mmol/minute/kPa (95% CI -0.35 to 0.12; P = 0.34). Lung density measured by computer tomography (CT) scan deteriorated significantly less in the treatment group than in the placebo group (mean difference (MD) 0.86 g/L, 95% CI 0.31 to 1.42; P = 0.002). Several secondary outcomes were unreported in the largest and most recent trial whose authors had numerous financial conflicts of interest.Authors' conclusionsThis review update added one new study and 143 new participants, but the conclusions remain unchanged. Due to sparse data, we could not arrive at a conclusion about the impact of augmentation therapy on mortality, exacerbations, lung infections, hospital admission and quality of life, and there was uncertainty about possible harms. Therefore, it is our opinion that augmentation therapy with alpha-1 antitrypsin cannot be recommended.

Project description:Rationale: The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is associated with chronic obstructive pulmonary disease (COPD), even among never-smokers. The SZ genotype is also considered severe; yet, its effect on lung health remains unclear.Objectives: To determine the effect of SZ-AATD on spirometry compared with a normal-risk population and to determine the effect of smoking cessation in this genotype.Methods: We prospectively enrolled 166 related individuals, removing lung index cases to reduce bias, and compared spirometry between 70 SZ and 46 MM/MS individuals (control subjects). The effect of AAT concentrations on outcomes was assessed in 82 SZ individuals (including lung index cases). Subsequently, we analyzed retrospective SZ registry data to determine the effect of smoking cessation on spirometry decline (n = 60) and plasma anti-neutrophil elastase capacity (n = 20).Measurements and Main Results: No difference between SZ and control never-smokers was seen. Ever smoking was associated with a lower FEV1% predicted (-14.3%; P = 0.0092) and a lower FEV1/FVC ratio (-0.075; P = 0.0041) in SZ-AATD. No association was found between AAT concentration and outcomes for SZ-AATD. Longitudinal analysis of 60 SZ individuals demonstrated that COPD at baseline, but not former smoking or AAT concentrations, predicted greater spirometry decline. Finally, anti-neutrophil elastase capacity did not differ between former smokers and never-smokers (P = 0.67).Conclusions: SZ never-smokers demonstrated no increased risk of COPD, regardless of AAT concentration. Smoking interacts with SZ-AATD to significantly increase airflow obstruction. Former smoking alone is not associated with greater spirometry decline in SZ-AATD, suggesting that cessation attenuates the obstructive process. We found no evidence that the putative protective threshold or AAT concentrations predict risk within the SZ genotype, raising further doubts over the need for intravenous AAT augmentation in this cohort.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets