High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity

Abstract

BackgroundAcetaminophen (APAP) overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1), and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI) at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration. This study aims to test whether blockade of HMGB1 improves hepatocyte regeneration after APAP overdose.MethodsMale C57BL/6 mice were treated with a single dose of APAP (350 mg/kg). 2 hrs after APAP administration, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose) or non-immune (sham) IgG every 24 hours for a total of 2 doses.Results24 hrs after APAP injection, anti-HMGB1 therapy instead of sham IgG therapy significantly improved hepatocyte regeneration microscopically; 48 hrs after APAP challenge, the sham IgG treated mice showed 14.6% hepatic necrosis; in contrast, blockade of HMGB1 significantly decreased serum transaminases (ALT and AST), markedly reduced the number of hepatic inflammatory cells infiltration and restored liver structure to nearly normal; this beneficial effect was associated with enhanced hepatic NF-κB DNA binding and increased the expression of cyclin D1, two important factors related to hepatocyte regeneration.ConclusionHMGB1 impairs hepatocyte regeneration after APAP overdose; Blockade of HMGB1 enhances liver recovery and may present a novel therapy to treat APAP overdose.

New Insights into the Acetaminophen Hepatotoxicity Research

“…Ringer's lactate solution (RLS) therapy and the anti-HMGB1 treatment enhance liver recovery at the late phase of APAP toxicity by increasing cyclin D1 expression [10,13]; in contrast, the Ethyl pyruvate (EP) therapy and the prolonged treatment with N-acetyl-cysteine (NAC) impair liver regeneration by decreasing cyclin D1 expression [9,14]. These reports support the notion that cyclin D1 is reliable to reveal liver regeneration during APAP hepatotoxicity.…”

“…Inhibition of NF-κB after partial hepatectomy results in massive hepatocyte apoptosis worsens liver injury and decreases survival [40]. There is evidence suggesting that the impact of APAP toxicity ensues, at least in part, by dramatic modulation of inflammatory and/ or regeneration programs [41], therefore, it is possible that in APAP overdose, enhanced NF-κB activation diverts intracellular pathways from those associated with inflammation and cell death to mechanisms linked to recruitment and activation of pro-regenerative programs, this notion is supported by following studies: enhanced NF-kB DNA binding is associated with improved liver recovery during the late phase of APAP hepatotoxicity [10,13]; in contrast, decreased NF-kB DNA binding is associated with impaired liver regeneration [14]. The role of NF-kB during the early injurious phase of APAP toxicity is still not clear.…”

“…HMGB1 plays an important role in modulating inflammatory cascade in activated macrophages: HMGB1 stimulates macrophages to release TNF-α and IL-6, while HMGB1neutralizing antibody can block TNF-α release [33,34] and knocking-out HMGB1 receptor can reverse IL-6 release [34]. Exogenous HMGB1 injection induces liver injury in normal mice [35]; HMGB1 impairs hepatocyte regeneration and blockade of HMGB1 improves liver regeneration in mice subjected to APAP overdose [13]; anti-HMGB1 treatment protects against APAP hepatotoxicity in rats [36]; in addition, HMGB1 mediates gut bacterial translocation (BT) during APAP hepatotoxicity [11].…”

“…Currently HE staining is not widely used to detect early hepatocyte regeneration; however, HE staining is reliable to reveal liver regeneration in C57/BL6 mice during APAP hepatotoxicity [11,13], and the pattern of hepatocyte regeneration revealed by HE staining does not match the liver proliferation revealed by BrdU/ PCNA methods [10,11,13], these results indicate that the conventional PCNA and BrdU methods are not reliable to reveal liver regeneration in C57/BL6 mice subjected to APAP overdose and other parameters are needed to detect liver repair in APAP toxicity.…”

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

“…It is also important to note that the release of the specific HMGB1 isoform such as acetylated HMGB1 is related to drug-induced liver injury prognosis in the patient and mouse model (89,90). Blocking HMGB1 release or activity by ethyl pyruvate and HMGB1-neutralizing antibody prevents APAP-induced hepatotoxicity and restores liver structure by inhibition of oxidative injury and inflammation (91,92). In addition, HMGB1 cytoplasmic translocation and release during tissue damage and cell death promotes pathological processes in several drug-induced acute liver failures (93,94).…”