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. 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. (Hepatology 2014;60:990–1002)

The therapeutic detoxification of chlorogenic acid against acetaminophen-induced liver injury by ameliorating hepatic inflammation

“…There are already reports demonstrate that TLR3 and TLR4 play critical roles in the progression of AP-induced hepatotoxicity [26,27]. In addition, there is report that benzyl alcohol attenuates AP-induced liver injury in a TLR4-dependent pattern in mice [28]. In the present study, CGA was found to inhibit AP-induced the activation of TLR3 and TLR4, which indicating that CGA may attenuate AP-induced hepatotoxicity via inhibiting TLR3 and TLR4.…”

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…Elevated levels of HMGB-1 were also observed in the liver biopsy samples from human alcoholic individuals compared to normal subjects . Elevated release of HMGB-1 and damage signaling were also observed in HFDexposed rats , APAP-induced DILI (Cai et al, 2014), and I/R injury (Kamo et al, 2013), although a few exceptions exist. For instance, one report indicated that hepatocyte-specific deletion of HMGB-1 worsens I/R liver injury , suggesting that HMGB-1 may play a dual role in regulating the cellular immune function, depending on the cellular context.…”

Biochanin A protects lipopolysaccharide/D-galactosamine-induced acute liver injury in mice by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation

“…IL-1β is a pro-inflammatory cytokine that plays a critical role in the development of hepatic failure [10]. IL-1β is produced as an inactivate form named as pro-IL-1β [11].…”