Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 24, Issue 20, Pages 11998-12007Publisher
WILEY
DOI: 10.1111/jcmm.15827
Keywords
alveolar epithelial cells; Emodin; epithelial-mesenchymal transition (EMT); neutrophil elastase (NE); Notch signalling; pulmonary fibrosis
Categories
Funding
- National Natural Science Foundation of China [81774231]
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The transition of alveolar type II epithelial cells into fibroblasts has been reported to cause and/or aggravate pulmonary fibrosis (PF), which is characterized by fibroblast proliferation, an enhanced production and accumulation of ECM (extracellular matrix), alveolar wall damage and functional capillary unit loss. Traditional Chinese medicine Emodin has been reported to inhibit TGF-beta-induced epithelial-mesenchymal transition (EMT) in alveolar epithelial cells through Notch signalling. In the present study, neutrophil elastase (NE, also known as ELA2) treatment promoted EMT, Notch1 cleavage (NICD/Notch1 ratio increase) and NICD nuclear translocation in RLE-6TN cells and A549 cells. The promotive roles of NE treatment in these events were significantly reversed by Notch1 knockdown. Traditional Chinese medicine Emodin treatment remarkably inhibited the enzyme activity of NE, suppressed EMT, Notch1 cleavage and NICD nuclear translocation within RLE-6TN and A549 cells, while NE treatment significantly reversed the effects of Emodin. Moreover, in RLE-6TN, the effects of NE on EMT, Notch1 cleavage and NICD nuclear translocation were remarkably attenuated by Emodin treatment and more attenuated by the combination of Emodin and neutrophil elastase inhibitor Sivelestat or notch signal pathway inhibitor DAPT. In conclusion, we revealed the involvement of NE-induced Notch1 cleavage in the functions of Emodin suppressing NE-caused EMT in RLE-6TN cells and A549 cells. This novel mechanism of Emodin inhibiting EMT might extend the application of Emodin in PF treatment.
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