Histone deacetylase regulates trypsin activation, inflammation, and tissue damage in acute pancreatitis in mice

Hannes Hartman, Erik Wetterholm, Henrik Thorlacius, Sara Regnér
Digestive Diseases and Sciences 2015, 60 (5): 1284-9

BACKGROUND: The onset of acute pancreatitis (AP) is characterized by early protease activation followed by inflammation and organ damage, but the mechanisms are poorly understood.

AIMS: We hypothesized that histone deacetylase (HDAC) inhibition might exert protective effects on AP and investigated the role of HDAC in trypsin activation, inflammation, and tissue damage in severe AP.

METHODS: Male C57Bl/6 mice were treated i.p. with the HDAC inhibitor trichostatin A (2 mg/kg) prior to retrograde infusion of taurocholic acid (5 %) into the pancreatic duct. Serum levels of amylase and interleukin (IL)-6, pancreatic levels of macrophage inflammatory protein-2 (MIP-2) as well as tissue morphology and myeloperoxidase activity in the pancreas and lung were determined 24 h after taurocholate challenge. Trypsin activation was analyzed in isolated acinar cells. Quantitative RT-PCR was used to examine the expression of pro-inflammatory mediators in the pancreas.

RESULTS: Pretreatment with trichostatin A decreased amylase levels by 70 % and protected against tissue injury in the pancreas. Moreover, HDAC inhibition reduced systemic IL-6 by more than 95 % and pulmonary myeloperoxidase activity by 75 %. Notably, inhibition of HDAC abolished taurocholate-induced gene expression of cyclooxygenase-2, MIP-2, monocyte chemotactic protein-1, IL-6, and IL-1β in the pancreas. In addition, HDAC inhibition reduced cerulein-induced trypsinogen activation in isolated acinar cells.

CONCLUSION: Our findings show that HDAC regulates trypsin activation, inflammation, and tissue damage in AP. Thus, targeting HDAC could serve as novel therapeutic approach in the management of severe AP.

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