INITIATION OF EXPERIMENTAL ACUTE PANCREATITIS AND MODULATION OF INFLAMMATORY RESPONSE
Heparan sulfate (HS), a substance common in the extracellular matrix on epithelial cells is present in the pancreas, lining the duct lumen. During pathological conditions, we propose that it can be shed from the ECM and bind to receptors on the cell surface, thus triggering an inflammatory response, which if excessive can cause acute pancreatitis (AP). Infusion of HS in the pancreatic duct in rats results in an inflammatory response without cellular damage, in similarity with lipopolysaccharide (LPS) infusion. The response differs though between the HS- and LPS-infusion both in regards to expressed chemokines and infiltrating cell types. HS-infusion predominantly causes early expression of CCL2 [monocyte chemoattractant protein-1 (MCP-1)] and subsequent early influx of monocytes. Increased expression of CXCL [cytokine-induced neutrophil chemoattractant-1 (CINC-1)] was not seen and neutrophils were shown to appear in the tissue later during the process. LPS, on the other hand, caused a rapid increase of CXCL (CINC-1) and also in early influx of neutrophils, in addition to similar patterns as HS-infusion of CCL2 (MCP-1) and monocytes. Taken together, the results indicate a receptor mediated innate immune response. Both HS and LPS has been shown to signal via the same receptor. We therefore suggest a difference in signaling pathways induced by the two ligands. Furthermore, the AP-induced systemic inflammation was studied. The anti-coagulant active site-inhibited factor VII (fVIIai) was shown to drastically decrease the inflammatory response. The effects in reducing neutrophil infiltration differed substantially between different organs. Nuclear factor kappa B (NF?B) activation was also shown to be affected by fVIIai. Pronounced differences between treatment effects was noted both depending on the studied organ and time point chosen. In conclusion a novel concept of the initiation of pancreatitis has been studied. The ducal epithelial cells are capable of signaling as a response to HS and LPS and to recruit inflammatory cells. This shows the importance of ductal cells and as a basis of new future pancreatitis specific interventions.
Source Type:Doctoral Dissertation
Keywords:MEDICINE; neutrophils; nuclear factor kappa B; monocytes; acute pancreatitis; ductal cells; active site-inhibited factor seven; heparan sulfate; lipopolysaccharide; innate immune response
Date of Publication:01/01/2008