Glycyrrhizin Prevents Liver Injury by Inhibition of High-Mobility Group Box 1 Production by Kupffer Cells after Ischemia-Reperfusion in Rats

Abstract

High-mobility group box 1 (HMGB1) acts as an early mediator of inflammation and organ damage in hepatic ischemia-reperfusion (I/R) injury. Glycyrrhizin is a natural anti-inflammatory and antiviral triterpene in clinical use. The purpose of this study was to investigate the effect of glycyrrhizin on liver injury caused by I/R and production of HMGB1 by Kupffer cells in rats. In the first test period, rats were given saline or glycyrrhizin 20 min before segmental hepatic warm I/R. Serum alanine aminotransferase and HMGB1 levels and hepatic histopathological findings were evaluated after I/R. Furthermore, expression of HMGB1 in the liver was assessed by immunohistochemical staining after I/R. Kupffer cells were isolated by collagenase digestion and differential centrifugation, and production of HMGB1 was assessed. In another set of experiments, the effect of inhibition of Kupffer cells by injection of liposome-entrapped dichloromethylene diphosphonate (lipo-MDP) on liver injury and expression of HMGB1 were investigated after I/R. Liver injury was prevented in the glycyrrhizin group compared with the control group. Furthermore, serum HMGB1 levels were also significantly blunted in the glycyrrhizin group compared with the control group. Cells expressing HMGB1 were detected in the hepatic sinusoid by immunohistochemistry and recognized morphologically as Kupffer cells. Furthermore, the expression of HMGB1 was reduced in the glycyrrhizin group compared with the control group. Production of HMGB1 was reduced in Kupffer cells isolated from the glycyrrhizin group compared with the control group. It is noteworthy that treatment with lipo-MDP significantly blunted serum HMGB1 levels and prevented liver injury after I/R. These results suggest that glycyrrhizin has the therapeutic potential to prevent warm I/R-induced injury during hepato-biliary surgery.

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

“…Blocking HMGB1 activity by HMGB1-neutralizing antibody increases cyclin D1 expression and improves hepatocyte regeneration in APAP-injected mice (92). Inhibition of HMGB1 release by glycyrrhizin also improves hepatocyte regeneration after I/R in rats (48). These studies suggest that extracellular HMGB1 limits liver regeneration, although the potential mechanism of this association still remains largely unknown.…”

“…Recent studies show that Bβ15-42 (the fibrin-derived peptide), PNU-282987 (a selective α7 nicotinic acetylcholine receptor agonist), EPC-K1 (the vitamin E derivative), melatonin, cisplatin and glycyrrhizin attenuate warm liver I/R damage partly through inhibition of HMGB1 release (47)(48)(49)(50)(51)(52). Interestingly, pretreatment of mice with HMGB1 protein significantly decreased liver I/R injury through upregulation of IL-1R-associated kinase-M, a negative regulator of TLR4 signaling (53).…”

Hypoxic Trophoblast HMGB1 Induces Endothelial Cell Hyperpermeability via the TRL-4/Caveolin-1 Pathway

“…Glycyrrhizic acid (GA), the main logic activities such as antioxidative, anti-inflammatory, antiulcerous, antidotal, antiallergic, antiviral, immunomodulating, hepatoprotective, and cardioprotective properties (19)(20)(21)(22). It was demonstrated that GA played an important role in the inhibition of HMGB1 (23,24); therefore, we also aimed to evaluate the effect of GA as an inhibitor of hypoxia trophoblast (including PMT and JEG-3) HMGB1 induced hyperpermeability of endothelial cells (ECs), including HUVECs and mouse arterial endothelial cells [MAECs].…”

High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling

“…Therefore, strategies disrupting TGF-b1/Smad signaling undoubtedly have therapeutic potential in the clinical treatment of PF. High-mobility group box 1 (HMGB1) is a transcription factor-like protein that acts as a danger signal in inflammatory diseases, tissue injury, as well as fibrotic diseases (Rowe et al, 2008;Ebina et al, 2011;Ogiku et al, 2011;Lee et al, 2013;Griffin et al, 2014;Li et al, 2014a). In lung tissues from patients with PF, HMGB1 is predominantly expressed in alveolar macrophages, infiltrating inflammatory cells, and epithelial cells (Hamada et al, 2008).…”