PMID- 23300006
OWN - NLM
STAT- MEDLINE
DCOM- 20130829
LR  - 20220129
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 132
IP  - 1
DP  - 2013 Mar
TI  - An in vitro model of human acute ethanol exposure that incorporates CXCR3- and 
      CXCR4-dependent recruitment of immune cells.
PG  - 131-41
LID - 10.1093/toxsci/kfs337 [doi]
AB  - Alcoholic liver disease (ALD) is one of the commonest causes of cirrhosis and 
      liver failure in the developed world. Hepatic inflammation is the critical stage 
      in progression of both ALD and non-ALD, but it remains difficult to study the 
      underlying mechanisms in a human system, and current animal models do not fully 
      recapitulate human liver disease. We developed a human tissue-based system to 
      study lymphocyte recruitment in response to ethanol challenge. Precision-cut 
      liver slices (PCLS) from human livers were incubated in culture, and hepatic 
      function was determined by albumin production, 
      3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide assay, glucose uptake 
      responses, and morphometric assessment. Responses of tissue and lymphocytes to 
      ethanol exposure were determined by PCR, flow cytometry, histology, and 
      lymphocyte infiltration assays. Human PCLS demonstrated appropriate upregulation 
      of CYP2E1, ADH1alpha, and ADH3 in response to ethanol treatment. Ethanol also induced 
      expression of endothelial VCAM-1 and ICAM-1, production of sICAM-1 and CXCL8, and 
      the chemokine receptors CXCR3 and CXCR4 on CD4 and CD8 lymphocytes. CXCR3- and 
      CXCR4-dependent migration of lymphocytes into the tissue increased significantly 
      in response to treatment with ethanol. We have demonstrated that ethanol 
      increases chemokine receptor expression and lymphocyte recruitment into human 
      liver tissue, suggesting that it may operate directly to promote hepatitis in 
      ALD. The physiological and pathophysiological responses of the PCLS to ethanol in 
      vitro highlight the potential of this assay for dissecting the molecular 
      mechanisms underlying human liver inflammation and as a screening tool for novel 
      therapeutics.
FAU - Karim, Sumera
AU  - Karim S
AD  - Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
FAU - Liaskou, Evaggelia
AU  - Liaskou E
FAU - Hadley, Samuel
AU  - Hadley S
FAU - Youster, Janine
AU  - Youster J
FAU - Faint, Jeff
AU  - Faint J
FAU - Adams, David H
AU  - Adams DH
FAU - Lalor, Patricia F
AU  - Lalor PF
LA  - eng
GR  - G0700301/MRC_/Medical Research Council/United Kingdom
GR  - G0300101/MRC_/Medical Research Council/United Kingdom
GR  - G0400496/MRC_/Medical Research Council/United Kingdom
GR  - BB/G529824/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - 5R01AA014257/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130108
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (CXCR3 protein, human)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (DNA Primers)
RN  - 0 (Receptors, CXCR3)
RN  - 0 (Receptors, CXCR4)
RN  - 3K9958V90M (Ethanol)
SB  - IM
MH  - Base Sequence
MH  - Cell Adhesion
MH  - DNA Primers
MH  - Ethanol/*toxicity
MH  - Humans
MH  - In Vitro Techniques
MH  - Lymphocytes/cytology/*drug effects
MH  - *Models, Biological
MH  - Polymerase Chain Reaction
MH  - Receptors, CXCR3/*physiology
MH  - Receptors, CXCR4/*physiology
PMC - PMC3576009
EDAT- 2013/01/10 06:00
MHDA- 2013/08/30 06:00
PMCR- 2014/03/01
CRDT- 2013/01/10 06:00
PHST- 2013/01/10 06:00 [entrez]
PHST- 2013/01/10 06:00 [pubmed]
PHST- 2013/08/30 06:00 [medline]
PHST- 2014/03/01 00:00 [pmc-release]
AID - kfs337 [pii]
AID - 10.1093/toxsci/kfs337 [doi]
PST - ppublish
SO  - Toxicol Sci. 2013 Mar;132(1):131-41. doi: 10.1093/toxsci/kfs337. Epub 2013 Jan 8.