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Inhibition of Class I histone deacetylases abrogates tumor growth factor β expression and development of fibrosis during chronic pancreatitis
Citation
Bombardo, M and Chen, R and Malagola, E and Saponara, E and Hills, AP and Graf, R and Sonda, S, Inhibition of Class I histone deacetylases abrogates tumor growth factor β expression and development of fibrosis during chronic pancreatitis, Molecular pharmacology, 94, (2) pp. 793-801. ISSN 0026-895X (2018) [Refereed Article]
Copyright Statement
Copyright 2018 by The American Society for Pharmacology and Experimental Therapeutics
DOI: doi:10.1124/mol.117.110924
Abstract
Pancreatic fibrosis is the hallmark of chronic pancreatitis, a highly debilitating disease for which there is currently no cure. The key event at the basis of pancreatic fibrosis is the deposition of extracellular matrix proteins by activated pancreatic stellate cells (PSCs). Transforming growth factor β (TGFβ) is a potent profibrotic factor in the pancreas as it promotes the activation of PSC; thus, pharmacologic interventions that effectively reduce TGFβ expression harbor considerable therapeutic potential in the treatment of chronic pancreatitis. In this study, we investigated whether TGFβ expression is reduced by pharmacologic inhibition of the epigenetic modifiers histone deacetylases (HDACs). To address this aim, chronic pancreatitis was induced in C57BL/6 mice with serial injections of cerulein, and the selective class 1 HDAC inhibitor MS-275 was administered in vivo in a preventive and therapeutic manner. Both MS-275 regimens potently reduced deposition of extracellular matrix and development of fibrosis in the pancreas after 4 weeks of chronic pancreatitis. Reduced pancreatic fibrosis was concomitant with lower expression of pancreatic TGFβ and consequent reduced PSC activation. In search of the cell types targeted by the inhibitor, we found that MS-275 treatment abrogated the expression of TGFβ in acinar cells stimulated by cerulein treatment. Our study demonstrates that MS-275 is an effective antifibrotic agent in the context of experimental chronic pancreatitis and thus may constitute a valid therapeutic intervention for this severe disease.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | histone deacetylases, chronic pancreatitis, TGF beta |
| Research Division: | Biological Sciences |
| Research Group: | Biochemistry and Cell Biology |
| Research Field: | Signal Transduction |
| Objective Division: | Health |
| Objective Group: | Clinical Health (Organs, Diseases and Abnormal Conditions) |
| Objective Field: | Digestive System Disorders |
| UTAS Author: | Hills, AP (Professor Andrew Hills) |
| UTAS Author: | Sonda, S (Dr Sabrina Sonda) |
| ID Code: | 127546 |
| Year Published: | 2018 |
| Web of Science® Times Cited: | 2 |
| Deposited By: | Health Sciences |
| Deposited On: | 2018-08-02 |
| Last Modified: | 2019-03-20 |
| Downloads: | 0 |
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