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. Sep-Oct 2017;17(5):689-697. doi: 10.1016/j.pan.2017.06.005. Epub 2017 Jun 10.

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.

Keywords: Acute pancreatitis; BET inhibition; Drug discovery; Epigenetics.

MeSH terms

  • Acute Disease
  • Amylases / blood
  • Amylases / metabolism
  • Animals
  • Benzodiazepines / pharmacology*
  • Bile Acids and Salts / toxicity*
  • Ceruletide / toxicity*
  • Cytokines / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Inflammation / prevention & control
  • Lung / enzymology
  • Male
  • Mice
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Pancreas / enzymology
  • Pancreas / pathology
  • Pancreatitis / chemically induced*
  • Pancreatitis / therapy
  • Peroxidase / genetics
  • Peroxidase / metabolism
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Taurolithocholic Acid / analogs & derivatives*
  • Taurolithocholic Acid / toxicity
  • Trypsin / metabolism

Substances

  • Bile Acids and Salts
  • Cytokines
  • Dner protein, mouse
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • Benzodiazepines
  • taurolithocholic acid 3-sulfate
  • Taurolithocholic Acid
  • molibresib
  • Ceruletide
  • Peroxidase
  • Amylases
  • Trypsin