Selective inhibition of BET proteins reduces pancreatic damage and systemic inflammation in bile acid- and fatty acid ethyl ester- but not caerulein-induced acute pancreatitis



Huang, Wei, Haynes, Andrea C, Mukherjee, Rajarshi, Wen, Li, Latawiec, Diane, Tepikin, Alexei V, Criddle, David N ORCID: 0000-0003-2952-8450, Prinjha, Rab K, Smithers, Nicholas and Sutton, Robert ORCID: 0000-0001-6600-562X
(2017) Selective inhibition of BET proteins reduces pancreatic damage and systemic inflammation in bile acid- and fatty acid ethyl ester- but not caerulein-induced acute pancreatitis. Pancreatology, 17 (5). 689 - 697.

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Abstract

Objectives To evaluate the therapeutic potential of I-BET-762, an inhibitor of the bromodomain and extra-terminal (BET) protein family, in experimental acute pancreatitis (AP). Methods AP was induced by retrograde infusion of taurolithocholic acid sulphate into the biliopancreatic duct (TLCS-AP) or 2 intraperitoneal (i.p.) injections of ethanol and palmitoleic acid 1 h apart (FAEE-AP) or 12 hourly i.p. injections of caerulein (CER-AP). In all treatment groups, I-BET-762 (30 mg/kg, i.p.) was administered at the time of disease induction and again 12 h later. AP severity was assessed at 24 h by serum biochemistry, multiple cytokines and histopathology. Results TLCS-AP, FAEE-AP and CER-AP resulted in characteristic elevations in serum amylase and cytokine levels, increased pancreatic trypsin and myeloperoxidase activity, typical pancreatic histopathological changes and lung injury. Treatment with I-BET-762 significantly reduced biochemical, cytokine and histopathological responses in TLCS-AP and FAEE-AP, but not CER-AP. Conclusions These results suggest that in different forms of AP there are significant differences in the epigenetic control of gene transcription contributing to the severity of disease responses. There is therapeutic potential in targeting bromodomains for the treatment of gallstone- and alcohol-related pancreatitis.

Item Type: Article
Uncontrolled Keywords: Acute pancreatitis, Epigenetics, BET inhibition, Drug discovery
Depositing User: Symplectic Admin
Date Deposited: 02 Aug 2018 10:42
Last Modified: 13 Aug 2022 12:15
DOI: 10.1016/j.pan.2017.06.005
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3024501