Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis

Abstract

The relationship between inflammation and proteolytic activation in pancreatitis is an unresolved issue in pancreatology. The purpose of this study was to define the influence of neutrophils on trypsinogen activation in severe AP. Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. For neutrophil depletion, an anti-Gr-1 antibody was administered before pancreatitis induction. Administration of the anti-Gr-1 antibody reduced circulating neutrophils by 97%. Pancreatic TAP and serum amylase levels increased 2 h and 24 h after induction of pancreatitis. Neutrophil depletion reduced pancreatic TAP and serum amylase levels at 24 h but not at 2 h after pancreatitis induction. Pancreatic MPO and infiltration of neutrophils, as well as MIP-2 levels, were increased 24 h after taurocholate infusion. Two hours after taurocholate administration, no significant pancreatic infiltration of neutrophils was observed. Injection of the anti-Gr-1 antibody abolished MPO activity, neutrophil accumulation, and MIP-2 levels, as well as acinar cell necrosis, hemorrhage, and edema in the pancreas at 24 h. Moreover, taurocholate-provoked tissue damage and MPO activity in the lung were normalized by neutrophil depletion. Intravital fluorescence microscopy revealed a 97% reduction of leukocytes in the pancreatic microcirculation after administration of the anti-Gr-1 antibody. Our data demonstrate that initial trypsinogen activation is independent of neutrophils, whereas later activation is dependent on neutrophils in the pancreas. Neutrophils are critical in mediating pancreatic and lung tissue damage in severe AP.

Depletion of Neutrophils Protects Against L-Arginine-Induced Acute Pancreatitis in Mice

“…Steer and colleagues found that in a choline-deficient ethionine (CDE) diet-induced mouse AP model, neutrophil depletion by pretreatment with antineutrophil serum reduces the severity of AP and completely prevents lung injury [13]. Another study by Regnér and co-workers showed that neutrophil depletion with the anti-Gr-1 antibody reduces the pancreatic trypsinogen activation peptide (TAP) level, plasma amylase and MPO activities in taurocholate-induced severe AP, confirming that neutrophils are critical in mediating pancreatic and lung tissue damage under these conditions [27]. The effects of neutrophil depletion on the L-arginine-induced mouse AP model presented in this study are consistent with previous findings.…”

Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis

“…For example, depletion of neutrophils markedly decreases tissue damage in AP (Abdulla et al, 2011). One recent study identified neutrophil-derived matrix metalloproteinase-9 as a potent stimulus for trypsin activation in acinar cells and tissue damage in AP .…”

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

“…The two phenomena appear to be independent and mediated by different factors (62)(63)(64). Awla et al (61) use the pharmacologic inhibitor CsA to demonstrate the importance of calcineurin pathways.…”