PT  - JOURNAL ARTICLE
AU  - Marta Bombardo
AU  - Rong Chen
AU  - Ermanno Malagola
AU  - Enrica Saponara
AU  - Andrew P Hills
AU  - Rolf Graf
AU  - Sabrina Sonda
TI  - Inhibition of class I histone deacetylases abrogates TGFβ expression and development of fibrosis during chronic pancreatitis
AID  - 10.1124/mol.117.110924
DP  - 2018 Jan 01
TA  - Molecular Pharmacology
PG  - mol.117.110924
4099  - http://molpharm.aspetjournals.org/content/early/2018/06/07/mol.117.110924.short
4100  - http://molpharm.aspetjournals.org/content/early/2018/06/07/mol.117.110924.full
AB  - 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 (PSC). Transforming growth factor β (TGFβ) is a potent pro-fibrotic 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 this aim, chronic pancreatitis was induced in C57BL/6 mice with serial injections of cerulein and the selective class I 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 four weeks of chronic pancreatitis. Reduced pancreatic fibrosis was concomitant with lower expression of pancreatic TGF βand consequent reduced PSC activation. In search of the cell types targeted by the inhibitor, we found that MS-275 treatment abrogated the expression of TGFβin acinar cells stimulated by cerulein treatment. Our study demonstrates that MS-275 is an effective anti-fibrotic agent in the context of experimental chronic pancreatitis and thus it may constitute a valid therapeutic intervention for this severe disease.