Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar-to-ductal metaplasia

Autor:	Marta, Bombardo, Enrica, Saponara, Ermanno, Malagola, Rong, Chen, Gitta M, Seleznik, Cecile, Haumaitre, Evans, Quilichini, Anja, Zabel, Theresia, Reding, Rolf, Graf, Sabrina, Sonda
Rok vydání:	2017
Předmět:	Male Metaplasia Time Factors Pyridines Mice Transgenic Acinar Cells Research Papers Histone Deacetylases Autoimmune Diseases ErbB Receptors Histone Deacetylase Inhibitors Mice Inbred C57BL Disease Models Animal Mice Pancreatitis Pancreatitis Chronic Acute Disease Benzamides Leukocytes Animals
Zdroj:	British journal of pharmacology. 174(21)
ISSN:	1476-5381
Popis:	Pancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study, we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease.We analysed HDAC regulation during cerulein-induced acute, chronic and autoimmune pancreatitis using different transgenic mouse models. The functional relevance of class I HDACs was tested with the selective inhibitor MS-275 in vivo upon pancreatitis induction and in vitro in activated macrophages and primary acinar cell explants.HDAC expression and activity were up-regulated in a time-dependent manner following induction of pancreatitis, with the highest abundance observed for class I HDACs. Class I HDAC inhibition did not prevent the initial acinar cell damage. However, it effectively reduced the infiltration of inflammatory cells, including macrophages and T cells, in both acute and chronic phases of the disease, and directly disrupted macrophage activation. In addition, MS-275 treatment reduced DNA damage in acinar cells and limited acinar de-differentiation into acinar-to-ductal metaplasia in a cell-autonomous manner by impeding the EGF receptor signalling axis.These results demonstrate that class I HDACs are critically involved in the development of acute and chronic forms of pancreatitis and suggest that blockade of class I HDAC isoforms is a promising target to improve the outcome of the disease.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=pmid________::0dc932f32f877dfea6caa13b371cb36d https://pubmed.ncbi.nlm.nih.gov/28832971 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.