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High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling.
J Pharmacol Exp Ther. 2015 Sep; 354(3):302-9.JP

Abstract

Epithelial-to-mesenchymal transition (EMT) is a crucial event in the cellular origin of myofibroblasts that secrete extracellular matrix in the progression of pulmonary fibrosis (PF). High-mobility group box 1 (HMGB1) is a novel mediator of EMT. However, whether this process involves the recognized transforming growth factor-β1 (TGF-β1)/Smad signaling that also contributes to EMT in PF has not yet been elucidated. Here, we developed a model of PF induced by bleomycin (BLM) in rats and conducted several simulation experiments in A549 (human) and RLE-6TN (rat) alveolar epithelial cell (AEC) lines to unravel the role of TGF-β1/Smad2/3 signaling in HMGB1-mediated EMT. We found that the levels of serum HMGB1 and lung hydroxyproline were severely elevated after BLM administration. Moreover, the protein expression of HMGB1, TGF-β1, phosphorylated Smad2/3 (p-Smad2/3), and mesenchymal markers including α-smooth muscle actin, vimentin, and type I collagen were significantly increased with the reduced protein expression of an epithelial marker (E-cadherin) in the rat model by Western blot or immunohistochemical analysis. In addition, the uptake of both exogenous TGF-β1 and HMGB1 by AECs could induce EMT; meanwhile, HMGB1 dramatically enhanced TGF-β1 expression and triggered Smad2/3 phosphorylation. In contrast, TGF-β1 deficiency evidently ameliorated HMGB1-mediated EMT with reduced p-Smad2/3 in A549 cells. It provides new insights that HMGB1 release from injured lungs promotes AEC damage through induction of the EMT process, in which TGF-β1/Smad2/3 signaling is activated and contributes to PF. These results suggest that HMGB1 may constitute a therapeutic target for developing antifibrotic agents for abnormal lung remodeling.

Authors+Show Affiliations

Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China (L.-C.L.); The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China (D.-L.L., J.G.); School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (X.-T.M., W.-H.C., W.-C.Z., J.L.); and School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People's Republic of China (D.-L.L., L.X., P.Z.).Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China (L.-C.L.); The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China (D.-L.L., J.G.); School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (X.-T.M., W.-H.C., W.-C.Z., J.L.); and School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People's Republic of China (D.-L.L., L.X., P.Z.).Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China (L.-C.L.); The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China (D.-L.L., J.G.); School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (X.-T.M., W.-H.C., W.-C.Z., J.L.); and School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People's Republic of China (D.-L.L., L.X., P.Z.).Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China (L.-C.L.); The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China (D.-L.L., J.G.); School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (X.-T.M., W.-H.C., W.-C.Z., J.L.); and School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People's Republic of China (D.-L.L., L.X., P.Z.).Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China (L.-C.L.); The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China (D.-L.L., J.G.); School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (X.-T.M., W.-H.C., W.-C.Z., J.L.); and School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People's Republic of China (D.-L.L., L.X., P.Z.).Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China (L.-C.L.); The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China (D.-L.L., J.G.); School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (X.-T.M., W.-H.C., W.-C.Z., J.L.); and School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People's Republic of China (D.-L.L., L.X., P.Z.).Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China (L.-C.L.); The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China (D.-L.L., J.G.); School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (X.-T.M., W.-H.C., W.-C.Z., J.L.); and School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People's Republic of China (D.-L.L., L.X., P.Z.).Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China (L.-C.L.); The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China (D.-L.L., J.G.); School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (X.-T.M., W.-H.C., W.-C.Z., J.L.); and School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People's Republic of China (D.-L.L., L.X., P.Z.) gaojianayfy@163.com lijun@ahmu.edu.cn.Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China (L.-C.L.); The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China (D.-L.L., J.G.); School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (X.-T.M., W.-H.C., W.-C.Z., J.L.); and School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People's Republic of China (D.-L.L., L.X., P.Z.) gaojianayfy@163.com lijun@ahmu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26126535

Citation

Li, Liu-Cheng, et al. "High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling." The Journal of Pharmacology and Experimental Therapeutics, vol. 354, no. 3, 2015, pp. 302-9.
Li LC, Li DL, Xu L, et al. High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling. J Pharmacol Exp Ther. 2015;354(3):302-9.
Li, L. C., Li, D. L., Xu, L., Mo, X. T., Cui, W. H., Zhao, P., Zhou, W. C., Gao, J., & Li, J. (2015). High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling. The Journal of Pharmacology and Experimental Therapeutics, 354(3), 302-9. https://doi.org/10.1124/jpet.114.222372
Li LC, et al. High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling. J Pharmacol Exp Ther. 2015;354(3):302-9. PubMed PMID: 26126535.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling. AU - Li,Liu-Cheng, AU - Li,De-Lin, AU - Xu,Liang, AU - Mo,Xiao-Ting, AU - Cui,Wen-Hui, AU - Zhao,Ping, AU - Zhou,Wen-Cheng, AU - Gao,Jian, AU - Li,Jun, Y1 - 2015/06/30/ PY - 2014/12/26/received PY - 2015/06/29/accepted PY - 2015/7/2/entrez PY - 2015/7/2/pubmed PY - 2015/10/7/medline SP - 302 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 354 IS - 3 N2 - Epithelial-to-mesenchymal transition (EMT) is a crucial event in the cellular origin of myofibroblasts that secrete extracellular matrix in the progression of pulmonary fibrosis (PF). High-mobility group box 1 (HMGB1) is a novel mediator of EMT. However, whether this process involves the recognized transforming growth factor-β1 (TGF-β1)/Smad signaling that also contributes to EMT in PF has not yet been elucidated. Here, we developed a model of PF induced by bleomycin (BLM) in rats and conducted several simulation experiments in A549 (human) and RLE-6TN (rat) alveolar epithelial cell (AEC) lines to unravel the role of TGF-β1/Smad2/3 signaling in HMGB1-mediated EMT. We found that the levels of serum HMGB1 and lung hydroxyproline were severely elevated after BLM administration. Moreover, the protein expression of HMGB1, TGF-β1, phosphorylated Smad2/3 (p-Smad2/3), and mesenchymal markers including α-smooth muscle actin, vimentin, and type I collagen were significantly increased with the reduced protein expression of an epithelial marker (E-cadherin) in the rat model by Western blot or immunohistochemical analysis. In addition, the uptake of both exogenous TGF-β1 and HMGB1 by AECs could induce EMT; meanwhile, HMGB1 dramatically enhanced TGF-β1 expression and triggered Smad2/3 phosphorylation. In contrast, TGF-β1 deficiency evidently ameliorated HMGB1-mediated EMT with reduced p-Smad2/3 in A549 cells. It provides new insights that HMGB1 release from injured lungs promotes AEC damage through induction of the EMT process, in which TGF-β1/Smad2/3 signaling is activated and contributes to PF. These results suggest that HMGB1 may constitute a therapeutic target for developing antifibrotic agents for abnormal lung remodeling. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/26126535/High_Mobility_Group_Box_1_Mediates_Epithelial_to_Mesenchymal_Transition_in_Pulmonary_Fibrosis_Involving_Transforming_Growth_Factor_��1/Smad2/3_Signaling_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=26126535 DB - PRIME DP - Unbound Medicine ER -