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J Surg Res. 2015 Apr;194(2):544-50. doi: 10.1016/j.jss.2014.10.056. Epub 2014 Nov 6.

Protective effect of suberoylanilide hydroxamic acid against lipopolysaccharide-induced liver damage in rodents.

Author information

1
School of Arts and Sciences, Tufts University, Medford, Massachusetts.
2
Harvard University, Cambridge, Massachusetts.
3
Trauma Translational & Clinical Research, Section of General Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
4
Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts.
5
Trauma Translational & Clinical Research, Section of General Surgery, University of Michigan Hospital, Ann Arbor, Michigan. Electronic address: alamh@med.umich.edu.
6
Trauma Translational & Clinical Research, Section of General Surgery, University of Michigan Hospital, Ann Arbor, Michigan. Electronic address: yqli@med.umich.edu.

Abstract

BACKGROUND:

Lipopolysaccharide (LPS) has a deleterious effect on several organs, including the liver, and eventually leads to endotoxic shock and death. LPS-induced hepatotoxicity is characterized by disturbed intracellular redox balance and excessive reactive oxygen species (ROS) accumulation, leading to liver injury. We have shown that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a murine model of LPS-induced shock, but the protective effect of SAHA against liver damage remains unknown. The goal of this study was to investigate the mechanism underlying SAHA action in murine livers.

METHOD:

Male C57BL/6J mice (6-8 wk), weighing 20-25 g, were randomly divided into three groups: (A) a sham group was given isotonic sodium chloride solution (10 μL/g body weight, intraperitoneal, i.p.) with dimethyl sulfoxide (DMSO; 1 μL/g body weight, i.p.); (B) an LPS group was challenged with LPS (20 mg/kg, i.p.) dissolved in isotonic sodium chloride solution with DMSO; (C) and an LPS plus SAHA group was treated with SAHA (50 mg/kg, i.p.) dissolved in DMSO immediately after injection of LPS (20 mg/kg, i.p.). Mice were anesthetized, and their livers were harvested 6 or 24 h after injection to analyze whether SAHA affected production of ROS and activation of apoptotic proteins in the liver cells of challenged mice.

RESULTS:

SAHA counteracted LPS-induced production of ROS (thiobarbituric acid reactive substances and nitrite) and reversed an LPS-induced decrease in antioxidant enzyme, glutathione. SAHA also attenuated LPS-induced hepatic apoptosis. Moreover, SAHA inhibited activation of the redox-sensitive kinase, apoptosis signal-regulating kinase-1, and the mitogen-activated protein kinases, p38 and Jun N-terminal kinase.

CONCLUSIONS:

Our data indicate, for the first time, that SAHA is capable of alleviating LPS-induced hepatotoxicity and suggest that a blockade of the upstream events required for apoptosis signal-regulating kinase-1 action may serve as a new therapeutic option in the treatment of LPS-induced inflammatory conditions.

KEYWORDS:

Apoptosis; Histone deacetylase inhibitor; Inflammation; LPS; Liver

PMID:
25479907
PMCID:
PMC4361238
DOI:
10.1016/j.jss.2014.10.056
[Indexed for MEDLINE]
Free PMC Article

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