PMID- 35104244
OWN - NLM
STAT- MEDLINE
DCOM- 20220411
LR  - 20240329
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 7
IP  - 5
DP  - 2022 Mar 8
TI  - Ferret models of alpha-1 antitrypsin deficiency develop lung and liver disease.
LID - 10.1172/jci.insight.143004 [doi]
LID - e143004
AB  - 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.
FAU - He, Nan
AU  - He N
AD  - Department of Anatomy and Cell Biology.
FAU - Liu, Xiaoming
AU  - Liu X
AD  - Department of Anatomy and Cell Biology.
FAU - Vegter, Amber R
AU  - Vegter AR
AD  - Department of Anatomy and Cell Biology.
FAU - Evans, T Idil A
AU  - Evans TIA
AD  - Department of Anatomy and Cell Biology.
FAU - Gray, Jaimie S
AU  - Gray JS
AD  - Department of Anatomy and Cell Biology.
FAU - Guo, Junfeng
AU  - Guo J
AD  - Department of Radiology.
FAU - Moll, Shashanna R
AU  - Moll SR
AD  - Department of Anatomy and Cell Biology.
FAU - Guo, Lydia J
AU  - Guo LJ
AD  - Department of Anatomy and Cell Biology.
FAU - Luo, Meihui
AU  - Luo M
AD  - Department of Anatomy and Cell Biology.
FAU - Ma, Ningxia
AU  - Ma N
AD  - Department of Anatomy and Cell Biology.
FAU - Sun, Xingshen
AU  - Sun X
AD  - Department of Anatomy and Cell Biology.
FAU - Liang, Bo
AU  - Liang B
AD  - Department of Anatomy and Cell Biology.
FAU - Yan, Ziying
AU  - Yan Z
AD  - Department of Anatomy and Cell Biology.
FAU - Feng, Zehua
AU  - Feng Z
AD  - Department of Anatomy and Cell Biology.
FAU - Qi, Lisi
AU  - Qi L
AD  - Department of Anatomy and Cell Biology.
FAU - Joshi, Arnav S
AU  - Joshi AS
AD  - Department of Surgery.
FAU - Shahin, Weam
AU  - Shahin W
AD  - Department of Anatomy and Cell Biology.
FAU - Yi, Yaling
AU  - Yi Y
AD  - Department of Anatomy and Cell Biology.
FAU - Gibson-Corley, Katherine N
AU  - Gibson-Corley KN
AD  - Department of Pathology, and.
FAU - Hoffman, Eric A
AU  - Hoffman EA
AD  - Department of Radiology.
FAU - Wang, Kai
AU  - Wang K
AD  - Department of Biostatistics, University of Iowa Carver College of Medicine, Iowa 
      City, Iowa, USA.
FAU - Mueller, Christian
AU  - Mueller C
AD  - Department of Pediatrics, University of Massachusetts Medical Center, Worcester, 
      Massachusetts, USA.
FAU - Engelhardt, John F
AU  - Engelhardt JF
AD  - Department of Anatomy and Cell Biology.
AD  - Department of Internal Medicine, University of Iowa Carver College of Medicine, 
      Iowa City, Iowa, USA.
FAU - Rosen, Bradley H
AU  - Rosen BH
AD  - Department of Anatomy and Cell Biology.
AD  - Department of Internal Medicine, University of Iowa Carver College of Medicine, 
      Iowa City, Iowa, USA.
LA  - eng
GR  - 75N92019C00010/HL/NHLBI NIH HHS/United States
GR  - T32 HL007638/HL/NHLBI NIH HHS/United States
GR  - P30 DK054759/DK/NIDDK NIH HHS/United States
GR  - R24 HL123482/HL/NHLBI NIH HHS/United States
GR  - KL2 TR002536/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220308
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
SB  - IM
MH  - Animals
MH  - Ferrets
MH  - Humans
MH  - Lung/metabolism
MH  - *Pulmonary Disease, Chronic Obstructive/metabolism
MH  - *Pulmonary Emphysema
MH  - *alpha 1-Antitrypsin Deficiency/complications/genetics/therapy
PMC - PMC8983124
OTO - NOTNLM
OT  - COPD
OT  - Genetic diseases
OT  - Proteases
OT  - Pulmonology
EDAT- 2022/02/02 06:00
MHDA- 2022/04/12 06:00
PMCR- 2022/03/08
CRDT- 2022/02/01 17:10
PHST- 2020/08/07 00:00 [received]
PHST- 2022/01/28 00:00 [accepted]
PHST- 2022/02/02 06:00 [pubmed]
PHST- 2022/04/12 06:00 [medline]
PHST- 2022/02/01 17:10 [entrez]
PHST- 2022/03/08 00:00 [pmc-release]
AID - 143004 [pii]
AID - 10.1172/jci.insight.143004 [doi]
PST - epublish
SO  - JCI Insight. 2022 Mar 8;7(5):e143004. doi: 10.1172/jci.insight.143004.