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)-β1, tumor necrosis factor (TNF)-α, 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)-β1 and α-smooth muscle actin (α-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.

Keywords: Bleomycin; HMGB1; MAPK/Smad3; glycyrrhizic acid; pulmonary toxicity.