PMID- 36256438
OWN - NLM
STAT- MEDLINE
DCOM- 20221201
LR  - 20221216
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Linking)
VI  - 323
IP  - 6
DP  - 2022 Dec 1
TI  - Characterization of hepatic inflammatory changes in a C57BL/6J mouse model of 
      alpha1-antitrypsin deficiency.
PG  - G594-G608
LID - 10.1152/ajpgi.00207.2022 [doi]
AB  - Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by a hepatic 
      accumulation of mutant alpha-1 antitrypsin (ZAAT). Individuals with AATD are 
      prone to develop a chronic liver disease that remains undiagnosed until late 
      stage of the disease. Here, we sought to characterize the liver pathophysiology 
      of a human transgenic mouse model for AATD with a manifestation of liver disease 
      compared with normal transgenic mice model. Male and female transgenic mice for 
      normal (Pi*M) and mutant variant (Pi*Z) human alpha-1 antitrypsin at 3 and 6 mo 
      of age were subjected to this study. The progression of hepatic ZAAT 
      accumulation, hepatocyte injury, steatosis, liver inflammation, and fibrotic 
      features were monitored by performing an in vivo study. We have also performed a 
      Next-Gene transcriptomic analysis of the transgenic mice liver tissue 16 h after 
      lipopolysaccharide (LPS) administration to delineate liver inflammatory response 
      in Pi*Z mice as compared with Pi*M. Our results show hepatic ZAAT accumulation, 
      followed by hepatocyte ballooning and liver steatosis developed at 3 mo in Pi*Z 
      mice compared with the mice carrying normal variant of human alpha-1 antitrypsin. 
      We observed higher levels of hepatic immune cell infiltrations in both 3- and 
      6-mo-old Pi*Z mice compared with Pi*M as an indication of liver inflammation. 
      Liver fibrosis was observed as accumulation of collagen in 6-mo-old Pi*Z liver 
      tissues compared with Pi*M control mice. Furthermore, the transcriptomic analysis 
      revealed a dysregulated liver immune response to LPS in Pi*Z mice compared with 
      Pi*M. Of particular interest for translational work, this study aims to establish 
      a mouse model of AATD with a strong manifestation of liver disease that will be a 
      valuable in vivo tool to study the pathophysiology of AATD-mediated liver 
      disease. Our data suggest that the human transgenic mouse model of AATD could 
      provide a suitable model for the evaluation of therapeutic approaches and 
      preventive reagents against AATD-mediated liver disease.NEW & NOTEWORTHY We have 
      characterized a mouse model of human alpha-1 antitrypsin deficiency with a strong 
      manifestation of liver disease that can be used as an in vivo tool to test 
      preventive and therapeutic reagents. Our data explores the altered 
      immunophenotype of alpha-1 antitrypsin-deficient liver macrophages and suggests a 
      relationship between acute inflammation, immune response, and fibrosis.
FAU - Khodayari, Nazli
AU  - Khodayari N
AUID- ORCID: 0000-0002-4659-1622
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, Florida.
FAU - Oshins, Regina
AU  - Oshins R
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, Florida.
FAU - Aranyos, Alek M
AU  - Aranyos AM
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, Florida.
FAU - Duarte, Sergio
AU  - Duarte S
AD  - Department of Surgery, College of Medicine, University of Florida, Gainesville, 
      Florida.
FAU - Mostofizadeh, Sayedamin
AU  - Mostofizadeh S
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida, Gainesville, Florida.
FAU - Lu, Yuanqing
AU  - Lu Y
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, Florida.
FAU - Brantly, Mark
AU  - Brantly M
AUID- ORCID: 0000-0003-0189-1565
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, Florida.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221018
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 (Lipopolysaccharides)
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
MH  - Male
MH  - Female
MH  - Humans
MH  - Mice
MH  - Animals
MH  - Mice, Inbred C57BL
MH  - Lipopolysaccharides
MH  - *alpha 1-Antitrypsin Deficiency/complications/genetics
MH  - alpha 1-Antitrypsin/genetics
MH  - *Fatty Liver
MH  - Mice, Transgenic
MH  - Disease Models, Animal
MH  - Inflammation
OTO - NOTNLM
OT  - animal model
OT  - inflammation
OT  - liver fibrosis
OT  - transcriptome
OT  - transgenic
EDAT- 2022/10/19 06:00
MHDA- 2022/12/02 06:00
CRDT- 2022/10/18 11:52
PHST- 2022/10/19 06:00 [pubmed]
PHST- 2022/12/02 06:00 [medline]
PHST- 2022/10/18 11:52 [entrez]
AID - 10.1152/ajpgi.00207.2022 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2022 Dec 1;323(6):G594-G608. doi: 
      10.1152/ajpgi.00207.2022. Epub 2022 Oct 18.