High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-ß1/Smad2/3 Signaling.
J Pharmacol Exp Ther
; 354(3): 302-9, 2015 Sep.
Article
en En
| MEDLINE
| ID: mdl-26126535
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-ß1 (TGF-ß1)/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-ß1/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-ß1, 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-ß1 and HMGB1 by AECs could induce EMT; meanwhile, HMGB1 dramatically enhanced TGF-ß1 expression and triggered Smad2/3 phosphorylation. In contrast, TGF-ß1 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-ß1/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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Fibrosis Pulmonar
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Transducción de Señal
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Proteína HMGB1
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Proteína Smad2
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Proteína smad3
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Factor de Crecimiento Transformador beta1
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Transición Epitelial-Mesenquimal
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Pharmacol Exp Ther
Año:
2015
Tipo del documento:
Article