Isoprenylation and NET formation in acute pancreatitis

Abstract: Acute Pancreatitis (AP) is an inflammation disease that characterized by activation of protease and the innate immune system, leading to infiltration of neutrophils and tissue damage in the pancreas. The aim of this thesis was to determine the role of isoprenylation (farnesyltransferase and geranylgeranyltransferase) as well as NET formation in regulating recruitment of neutrophils and tissue damage in severe AP. AP in mice was induced by retrograde infusion of Na-taurocholate into the pancreatic duct and intraperitoneal injection of L-arginine two times at hourly intervals. Induction of pancreatitis provoked a clear cut increase in tissue damage of the pancreas characterized by neutrophil infiltration, myeloperoxidase activity, chemokine levels, and acinar cell necrosis and edema formation in the pancreas. In paper I, farnesyltransferase mediates leukocyte sequestration and tissue injury in AP. Inhibition of farnesyltransferase attenuates infiltration of neutrophils in the pancreas and the lung and suggesting that farnesyltransferase controls both local and systemic inflammation in pancreatitis. Paper II demonstrates that geranylgeranyltransferase regulate severity in pancreatitis. Inhibition of geranylgeranyltransferase results in a reduction of neutrophil up-regulation Mac-1 and CXCL2 formation in the pancreas. Blocking geranylgeranyltransferase activity attenuated systemic inflammation and pulmonary neutrophils in animals with pancreatitis. In paper Paper III address the role of Ras-signalling in AP. Ras inhibition improves neutrophil infiltration, blood amylase, cytokine formation and and pancreatitis-associated systemic inflammation. Paper IV demonstrates that NETs are generated in the inflamed pancreas and play a critical role in the development of severe AP. Inhibition of NET decreased CXCL2 formation and neutrophil recruitment in the inflamed pancreas. Moreover, NETs regulates STAT3 activity and trypsin activation in acinar cells and histones might be important molecular mediators in these processes. These findings identify a novel role of isoprenylation and NET formation in pancreatitis and suggest that targeting these mechanisms might be a useful way to ameliorate local and systemic inflammation in severe AP.