title: Histone deacetylase regulates trypsin activation, inflammation, and tissue damage in acute pancreatitis in mice.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Sciences Malmö, Section of Surgery, Skåne University Hospital, Lund University, Inga-Marie Nilssons Gata 46, 205 02, Malmö, Sweden, Hannes.Hartman@med.lu.se.
authors.forename: Hannes
authors.initials: H
authors.lastname: Hartman
authors.forename: Erik
authors.initials: E
authors.lastname: Wetterholm
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
authors.forename: Sara
authors.initials: S
authors.lastname: Regnér
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002108:Ceruletide / Q000494:pharmacology; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D004789:Enzyme Activation; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008168:Lung / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010195:Pancreatitis / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009195:Peroxidase / Q000378:metabolism; D015398:Signal Transduction; D013656:Taurocholic Acid; D014357:Trypsin / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018836:Inflammation Mediators; D015850:Interleukin-6; C577686:interleukin-6, mouse; C012589:trichostatin A; D013656:Taurocholic Acid; D002108:Ceruletide; D009195:Peroxidase; D000681:Amylases; D014357:Trypsin; D006655:Histone Deacetylases