title: Benzyl alcohol attenuates acetaminophen-induced acute liver injury in a Toll-like receptor-4-dependent pattern in mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Central Hospital of Wuhan, Wuhan, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Changchun
authors.initials: C
authors.lastname: Cai
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Sean
authors.initials: S
authors.lastname: Whelan
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kautza
authors.forename: Jason
authors.initials: J
authors.lastname: Luciano
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Chen
authors.forename: Sladjana
authors.initials: S
authors.lastname: Stratimirovic
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D019905:Benzyl Alcohol / Q000627:therapeutic use*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D024243:HMGB1 Protein / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology*
chemical_list: D018712:Analgesics, Non-Narcotic; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000082:Acetaminophen; D019905:Benzyl Alcohol