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

Bombardo, M, Saponara, E, Malagola, E, Chen, R, Seleznik, G, Haumaitre, C, Quilichini, E, Zabel, A, Reding, T, Graf, R and Sonda, S ORCID: 0000-0001-8152-3425 2017 , 'Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar-to-ductal metaplasia' , British journal of pharmacology, vol. 174, no. 21 , pp. 3865-3880 , doi: 10.1111/bph.13984.

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Abstract

Background and purpose: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.Experimental logic: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.Key results: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.Conclusions and implications: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.

Item Type: Article
Authors/Creators:Bombardo, M and Saponara, E and Malagola, E and Chen, R and Seleznik, G and Haumaitre, C and Quilichini, E and Zabel, A and Reding, T and Graf, R and Sonda, S
Keywords: Histone deacetylases, acute pancreatitis, regeneration
Journal or Publication Title: British journal of pharmacology
Publisher: Nature Publishing Group
ISSN: 0007-1188
DOI / ID Number: 10.1111/bph.13984
Copyright Information:

© 2017 The British Pharmacological Society

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