Neogambogic acid prevents silica-induced fibrosis via inhibition of high-mobility group box 1 and MCP-1-induced protein 1.
Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO2); early stages are characterized by alveolar inflammation, and later stages are characterized by progressive lung fibrosis. Mounting evidence indicates that high-mobility group box 1 (HMGB1) is involved in pulmonary fibrosis. Whether neogambogic acid (NGA) inhibits macrophage and fibroblast activation induced by SiO2 by targeting HMGB1 remains unclear.



Experiments using cultured mouse macrophages (RAW264.7 cells) demonstrated that SiO2 treatment induces the expression of HMGB1 in a time- and dose-dependent manner via mitogen-activated protein kinases (MAPKs) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; in turn, this expression causes macrophage apoptosis and fibroblast activation. Pretreating macrophages with NGA inhibited the HMGB1 expression induced by SiO2 and attenuated both macrophage apoptosis and fibroblast activation. Moreover, NGA directly inhibited MCP-1-induced protein 1 (MCPIP1) expression, as well as markers of fibroblast activation and migration induced by SiO2. Furthermore, the effects of NGA on macrophages and fibroblasts were confirmed in vivo by exposing mice to SiO2.



NGA can prevent SiO2-induced macrophage activation and apoptosis via HMGB1 inhibition and SiO2-induced fibrosis via the MCPIP1 pathway. Targeting HMGB1 and MCPIP1 with NGA could provide insights into the potential development of a therapeutic approach for alleviating the inflammation and fibrosis induced by SiO2.
Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China; Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Wei
W
Zhang
Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China. Electronic address: meizhang1717@163.com.
Mei
M
Zhang
Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Zhongjiang
Z
Wang
Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Yusi
Y
Cheng
Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Haijun
H
Liu
Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Zewei
Z
Zhou
Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Bing
B
Han
Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Baoan
B
Chen
Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China. Electronic address: yaohh@seu.edu.cn.
Honghong
H
Yao
Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China; Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China. Electronic address: chaojie@seu.edu.cn.
Jie
J
Chao
D000818:Animals; D002460:Cell Line; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000517:prevention & control*; D012260:Ribonucleases / Q000037:antagonists & inhibitors*; D012822:Silicon Dioxide / Q000633:toxicity*; D014966:Xanthenes / Q000494:pharmacology*
D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D014966:Xanthenes; D012822:Silicon Dioxide; C045863:neo-gambogic acid; D012260:Ribonucleases; C541320:Zc3h12a protein, mouse
HMGB1; MCPIP1; Neogambogic acid; Silicosis