Glycyrrhizic acid, as an inhibitor of HMGB1, alleviates bleomycin-induced pulmonary toxicity in mice through the MAPK and Smad3 pathways

Abstract

Aim: High-mobility group box 1 (HMGB1) protein has been noticed particularly for its pivotal role in several pathologies. However, the relevance between HMGB1 and pathological progress in lung toxicity still remains unclear. In the study, we evaluated the effect of glycyrrhizic acid as an HMGB1 inhibitor on the early inflammation and late fibrosis in bleomycin-induced pulmonary toxicity in mice. Methods: We established a bleomycin-induced pulmonary toxicity model to detect the relevance between HMGB1 and pathological changes in the early inflammatory and late fibrotic stages. Results: We found that bleomycin-induced increase in inflammatory cytokines interleukin (IL)-b1, tumor necrosis factor (TNF)-a, monocyte chemotactic protein (MCP)-1, and inflammatory lesions in lung tissue in the early stage of the model. However, markers of fibrosis such as transforming growth factor (TGF)-b1 and a-smooth muscle actin (a-SMA) were significantly elevated on day 7 after bleomycin instillation. Interestingly, HMGB1 also began to rise on day 7, rather than in the early inflammatory phase. However, early (from day 0 to 14 after bleomycin instillation) or late (from day 14 to 28) intervention with HMGB1 neutralizing antibody or glycyrrhizic acid alleviated inflammation and fibrosis through down-regulating the inflammatory signaling mitogen-activated protein kinase (MAPK) and fibrotic signaling Smad3 pathway. Conclusion: Our results suggested that HMGB1 mediates both inflammation and fibrosis in this model. The development of high-potency and low-toxicity HMGB1 inhibitors may be a class of potential drugs for the treatment of pulmonary fibrosis.

Glycyrrhizic Acid Attenuates Pulmonary Fibrosis of Silicosis by Inhibiting the Interaction between HMGB1 and BRG1 through PI3K/Akt/mTOR Pathway

“…Among the inhibitors targeting HMGB1, glycyrrhizic acid is the most widely used and the most effective, so this study chose glycyrrhizic acid as an intervention to explore its intervention effect and mechanism on experimental silicosis in mice. Studies have shown that HMGB1 exists in the early stages of pulmonary inflammation and late fibrosis, and glycyrrhizic acid inhibits the expression of HMGB1, which can slow down the progression of pulmonary inflammation and fibrosis [ 15 ]. Glycyrrhizic acid can not only inhibit SMAD2 and SMAD3 pathways mediated by TGF-β1 [ 39 ], but can also change the pathological morphology of the bile duct ligation model and prevent liver fibrosis [ 40 ].…”

“…Glycyrrhizic acid is an HMGB1 inhibitor [ 14 ], which is approved by FDA to treat hepatitis. Some studies have shown that HMGB1 exists in the early stage of pulmonary inflammation and late fibrosis, and glycyrrhizic acid inhibits the expression of HMGB1, which limits the progress of pulmonary toxicity [ 15 ]. Previous studies have shown that glycyrrhizin inhibits HMGB1 and thus inhibits EMT by blocking the downstream Smad2/3 signal pathway [ 16 ], but there is no study on glycyrrhizic acid in silica-induced silicosis in mice.…”

The Use of Herbal Medicines for the Prevention of Glucocorticoid-Induced Osteoporosis

“…By suppressing signaling through the Smad3 and MAPK pathways, for example, glycyrrhizin (30 and 100 mg/kg for a period of 28 days, i.g.) has been shown to reduce the severity of bleomycin-induced inflammation and pulmonary fibrosis in mice ( 49 ). Glycyrrhizin (10 mg/kg for once every day in the first 3 weeks following by given once every 3 days until the twelfth week, intra-articular knee injection) treatment can also alleviate inflammation and the degeneration of cartilage tissue in a rat model of osteoarthritis via regulating the TLR4/NF-κB and HMGB1 pathways ( 50 ).…”

The Role of Supplementation with Natural Compounds in Post-Stroke Patients

“…The biological activity of glycyrrhizin is primarily associated with anti-inflammatory, anti-allergic, hepatoprotective, antitumor and antiviral effects [ 163 ]. The anti-inflammatory effect of glycyrrhizin is expressed by inhibition of high mobility group box chromosomal protein 1 (HMGB1) [ 164 ]. In the acute phase of stroke, stimulation of the effectors of the innate immune response responsible for the removal of dead cells is observed.…”