November 12, 2014
Notes: Gu, Haitao
Buchler, Markus W
Whitcomb, David C
Research Support, Non-U.S. Gov’t
Am J Pathol. 2013 Nov;183(5):1508-17. doi: 10.1016/j.ajpath.2013.07.023. Epub 2013 Sep 30.
Author Address: Department of General, Visceral, and Transplantation Surgery, University Clinic Heidelberg, Heidelberg, Germany.
Reference Type: Journal Article
Record Number: 4894Author: Gu, H., Werner, J., Bergmann, F., Whitcomb, D. C., Buchler, M. W. and Fortunato, F.
Title: Necro-inflammatory response of pancreatic acinar cells in the pathogenesis of acute alcoholic pancreatitis
Journal: Cell Death Dis
Short Title: Necro-inflammatory response of pancreatic acinar cells in the pathogenesis of acute alcoholic pancreatitis
Alternate Journal: Cell death & disease
ISSN: 2041-4889 (Electronic)
Accession Number: 24091659
Keywords: Acinar Cells/metabolism/*pathology
Disease Models, Animal
Intracellular Space/drug effects/metabolism
Toll-Like Receptor 4/metabolism
Abstract: The role of pancreatic acinar cells in initiating necro-inflammatory responses during the early onset of alcoholic acute pancreatitis (AP) has not been fully evaluated. We investigated the ability of acinar cells to generate pro- and anti-inflammatory mediators, including inflammasome-associated IL-18/caspase-1, and evaluated acinar cell necrosis in an animal model of AP and human samples. Rats were fed either an ethanol-containing or control diet for 14 weeks and killed 3 or 24 h after a single lipopolysaccharide (LPS) injection. Inflammasome components and necro-inflammation were evaluated in acinar cells by immunofluorescence (IF), histology, and biochemical approaches. Alcohol exposure enhanced acinar cell-specific production of TNFalpha, IL-6, MCP-1 and IL-10, as early as 3 h after LPS, whereas IL-18 and caspase-1 were evident 24 h later. Alcohol enhanced LPS-induced TNFalpha expression, whereas blockade of LPS signaling diminished TNFalpha production in vitro, indicating that the response of pancreatic acinar cells to LPS is similar to that of immune cells. Similar results were observed from acinar cells in samples from patients with acute/recurrent pancreatitis. Although morphologic examination of sub-clinical AP showed no visible signs of necrosis, early loss of pancreatic HMGB1 and increased systemic levels of HMGB1 and LDH were observed, indicating that this strong systemic inflammatory response is associated with little pancreatic necrosis. These results suggest that TLR-4-positive acinar cells respond to LPS by activating the inflammasome and producing pro- and anti-inflammatory mediators during the development of mild, sub-clinical AP, and that these effects are exacerbated by alcohol injury.