NEUTROPHIL EXTRACELLULAR TRAPS TRIGGER TRYPSIN ACTIVATION, PATHOLOGICAL INFLAMMATION AND TISSUE DAMAGE IN SEVERE ACUTE PANCREATITIS

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Henrik Thorlacius
Department of of Surgery, Malmö, Lund University, 205 02 Malmö, Sweden

ABSTRACT
Objective: Neutrophils play a pivotal role in local and systemic complications of acute pancreatitis (AP), but the mechanisms regulating neutrophil-induced tissue damage in the inflamed pancreas is not fully understood. Recently, neutrophil extracellular traps (NETs) have been demonstrated to contribute to organ dysfunction in both infective and non-infective diseases. In the present study, we investigated the role of NETs in AP.
Methods: AP was induced in male C57BL/6 mice by infusion of taurocholate into the pancreatic duct. Extracellular DNA was stained by Sytox green and NET formation was quantified by confocal microscopy. To analyze the impact of NET formation in AP, NET depletion was induced by DNAse I administration. In separate experiments isolated acinar cells were exposed to NETs.
Results: Taurocholate challenge evoked formation of NET in the pancreas and increased cell-free DNA in plasma. Formation of macrophage inflammatory protein-2 (CXCL2), neutrophil infiltration and tissue damage in the inflamed pancreas and lung were significantly attenuated by DNAse I treatment. Moreover, DNAse I administration markedly reduced levels of blood amylase, CXCL-2, interleukin-6 and high-mobility groups protein 1 as well as macrophage-1 antigen expression on circulating neutrophils in mice with pancreatitis. NETs triggered trypsin formation and activation of signal transducer and activator of transcription-3 in isolated acinar cells. Histones increased trypsin activation and pre-incubation of NETs with polysialic acid abolished NET-induced activation of trypsin in acinar cells, suggesting that histones are responsible for great part of NET-induced trypsin activation.
Conclusions: Taken together, NET formation regulates local and remote organ inflammation and damage in AP. These novel findings provide new insights in the pathophysiology of pancreatitis and indicate that targeting NETs might be an effective way to ameliorate tissue damage severe AP.

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