Inflammatory response and intervention in experimental acute pancreatitis

Abstract: Acute pancreatitis (AP) is a common disease where underlying mechanisms for the local initiating events in the pancreas, the systemic dissemination of the inflammatory response and remote organ dysfunction still are unclear. The overall aim of the thesis was to study mechanisms of the inflammatory response in AP with special emphasis on local, systemic, and distant organ injury directed at different signalling pathways, and potential therapeutic strategies to prevent the development of inflammation and cell injury following AP. Experimental AP was induced by the intraductal administration of 5% sodium taurodeoxycholate in SD rats. Treatment attempts with NF-?B inhibitors (NAC and PDTC), ERK inhibitor (PD-98059), tyrosine kinase inhibitor (genistein), protease inhibitors (aprotinin, pefabloc, and trypsin inhibitor), and PKC inhibitors (polymyxin B and staurosporine) were tested. AP induced local pancreatic inflammation and injury, with increased levels of IL-6, CINC, and MCP-1 in pancreatic acini, and neutrophil accumulation in the pancreas. In parallel, an inflammatory response in the lungs was observed. However, a hyporesponsiveness in circulating monocytes occurred. Moreover, a reverse relationship of the expression of NF-?B, cytokine and chemokine mRNA in pancreatic acini and circulating monocytes exists and cytokines and chemokines are primarily produced by the local inflamed compartment rather than by circulating monocytes. This indicates that SIRS predominates within the inflamed tissues, in parallel with a downregulation of circulating monocytes. Consequently, comparing the immune status and inflammatory response of circulating monocytes and pancreatic acini may provide understanding of mechanisms by which SIRS, CARS and MODS potentially develop in severe AP. This process was closely regulated by NF-?B. The use of an immune stimulator delivered systemically in cases of immune suppression of monocytes could be of potential benefit. Various inhibitors targeting the different signalling pathways could prevent AP-induced local, systemic, and distant organ inflammatory responses. In addition, we further investigated PKC signalling transduction in AP-induced lung injury. Our results showed that an activation of the PKC signalling transduction could play an important role in the pathogenesis of pancreatitis-associated lung injury and that the PKC inhibitor polymyxin B prevented against AP-induced lung injury.