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Benzyl alcohol attenuates acetaminophen‐induced acute liver injury in a Toll‐like receptor‐4‐dependent pattern in mice
Author(s) -
Cai Changchun,
Huang Hai,
Whelan Sean,
Liu Li,
Kautza Benjamin,
Luciano Jason,
Wang Guoliang,
Chen Guoqiang,
Stratimirovic Sladjana,
Tsung Allan,
Billiar Timothy R.,
Zuckerbraun Brian S.
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27201
Subject(s) - inflammasome , liver injury , acetaminophen , tlr4 , pharmacology , medicine , rage (emotion) , receptor , signal transduction , chemistry , biology , biochemistry , neuroscience
Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in industrialized countries. Understanding the mechanisms of APAP‐induced liver injury as well as other forms of sterile liver injury is critical to improve the care of patients. Recent studies demonstrate that danger signaling and inflammasome activation play a role in APAP‐induced injury. The aim of these investigations was to test the hypothesis that benzyl alcohol (BA) is a therapeutic agent that protects against APAP‐induced liver injury by modulation of danger signaling. APAP‐induced liver injury was dependent, in part, on Toll‐like receptor (TLR)9 and receptor for advanced glycation endproducts (RAGE) signaling. BA limited liver injury over a dose range of 135‐540 μg/g body weight or when delivered as a pre‐, concurrent, or post‐APAP therapeutic. Furthermore, BA abrogated APAP‐induced cytokines and chemokines as well as high‐mobility group box 1 release. Moreover, BA prevented APAP‐induced inflammasome signaling as determined by interleukin (IL)‐1β, IL‐18, and caspase‐1 cleavage in liver tissues. Interestingly, the protective effects of BA on limiting liver injury and inflammasome activation were dependent on TLR4 signaling, but not TLR2 or CD14. Cell‐type–specific knockouts of TLR4 were utilized to further determine the protective mechanisms of BA. These studies found that TLR4 expression specifically in myeloid cells (LyzCre‐ tlr4 −/− ) were necessary for the protective effects of BA. Conclusion : BA protects against APAP‐induced acute liver injury and reduced inflammasome activation in a TLR4‐dependent manner. BA may prove to be a useful adjunct in the treatment of APAP and other forms of sterile liver injury. (H epatology 2014;60:990–1002)