Publication: Protective role of antithrombin in mouse models of liver injury
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Date
2012
Authors
Teruel, Raul ; Martínez, Constantino ; Arcas, Isabel ; Martínez-Martínez, Irene ; Morena-Barrio, María Eugenia de la ; Vicente, Vicente ; Corral, Javier ; Guerrero López, José Antonio
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Publisher
Elsevier
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DOI
https://doi.org/10.1016/j.jhep.2012.06.023
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info:eu-repo/semantics/article
Description
Acceso restringido
Abstract
Background & Aims: Coagulopathy caused by an imbalance
of hemostatic factors is associated with the pathophysiology
of liver disease. We have investigated the role of antithrombin
(AT), a key anticoagulant serpin, in the onset of liver
disease.
Methods: Liver injury was induced by CCl4 injection and bile duct
ligation (BDL) in wild type (WT) and AT-deficient (AT+/ ) mice.
Twenty-four hours after CCl4 treatment, aspartate-transaminase,
alanine-transaminase, liver lesion size, leukocyte infiltration, and
apoptosis were reduced in WT animals compared to AT+/ mice.
Results: Administration of exogenous AT in AT+/ animals did not
restore the values observed in WT mice, suggesting that intrahepatic
AT might also offer protection against CCl4. In the BDL
model, increased liver injury was also evident in AT+/ compared
to WT mice. An 85 kDa covalent complex involving AT was identified
in immunoblottings of liver lysates from CCl4-treated animals.
This complex was also present in anoikis hepatocytes and
H2O2-treated HepG2 cells, suggesting a role for AT in apoptosis.
Expression of recombinant WT–AT by HEK-EBNA cells increased
cell survival while expression of AT mutants, DR393 and R47C,
did not modify viability. Finally, plasma anti-FXa activity was
attenuated by liver injury, with AT+/ animals showing a greater
reduction than WT mice.
Conclusions: Our study reveals a protective role of AT against
liver injury due to its recognized anticoagulant and antiinflammatory
action. AT may also act via a previously unrecognized
antiapoptotic effect. The clinical implications of AT
deficiency in patients with liver disease should be further
addressed.
2012 European Association for the Study of the Liver. Published
by Elsevier B.V. All rights reserved.
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Citation
Journal of Hepatology 2012 57(5): 980-6
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