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Objective. Cytokines initiate and modify systemic inflammatory response in early acute pancreatitis. The aim of this study was to analyze which cytokines are released from the pancreas to portal venous blood in the early phase of acute experimental necrotizing and oedematous pancreatitis and which of those cytokines are correlated with the more severe form of the disease. Material and methods. Fifteen pigs were randomized to develop mild oedematous pancreatitis (n = 5, saline infusion to pancreatic duct), severe necrotizing pancreatitis (n = 5, taurocholic acid infusion) along with a control group (n = 5). Arterial and venous blood samples were drawn and cytokine levels were measured from portal vein blood at 0, 120, 240 and 360 min after the induction of pancreatitis. Tissue samples from the pancreas were harvested at 0 and 360 min. Results. White blood cell count increased in necrotizing pancreatitis and the control group. The amount of neutrophils increased ( p < 0.001) and the lymphocyte and eosinophil counts decreased in all groups ( p < 0.001, p < 0.001). The monocyte count, as well as PDGF and IL-6 concentrations, increased only in necrotizing pancreatitis. IL-8 and eotaxin increased both in oedematous and necrotizing pancreatitis. MCP-1 increased in all groups. IL-9, IL-4, MIP-1α, IFN- γ concentrations did not change. Eotaxin and MCP-1 plasma levels from a previous series between portal venous and pulmonary arterial blood were not significantly different. Conclusions. The initial inflammatory process was diverse in oedematous and necrotizing pancreatitis. Increased monocyte count in combination with elevated PDGF and IL-6 are characteric of necrotizing pancreatitis in our model. [ABSTRACT FROM AUTHOR]

Previously, we found that the University of North Carolina cystic fibrosis (UNC-CF) mouse had more severe experimental acute pancreatitis (AP) than wild-type (WT) mice characterized by exuberant pancreatic inflammation and impaired acinar apoptosis. Because exon 10 CFTR gene mutations exhibit different phenotypes in tissues such as the mouse lung, we tested the hypothesis that ΔF508-CF mice also develop severe AP associated with an antiapoptotic acinar phenotype, which requires indirect effects of the extracellular milieu. We used cerulein hyperstimulation models of AP. More severe pancreatitis occurred in cerulein-injected ΔF508-CF vs. WT mice based on histological severity (P < 0.01) and greater neutrophil sequestration [P < 0.0001; confirmed by myeloperoxidase activity (P < 0.005)]. In dispersed acini cerulein-evoked necrosis was greater in ΔF508-CF acini compared with WT (P < 0.05) and in WT acini pretreated with CFTRinh-172 compared with vehicle (P < 0.05). Cerulein-injected ΔF508-CF vs. WT mice had less apoptosis based on poly(ADP-ribose) polymerase (PARP) cleavage (P < 0.005), absent DNA laddering, and reduced terminal deoxynucleotidyltransferase biotin-dUTP nick end labeling (TUNEL) staining (P < 0.005). Unexpectedly, caspase-3 activation was greater in ΔF508-CF vs. WT acini at baseline (P < 0.05) and during AP (P < 0.0001). Downstream, ΔF508-CF pancreas overexpressed the X-linked inhibitor of apoptosis compared with WT (P < 0.005). In summary, the ΔF508-CF mutation, similar to the UNC-CF "null" mutation, causes severe AP characterized by an exuberant inflammatory response and impaired acinar apoptosis. Enhanced acinar necrosis in ΔF508-CF occurs independently of extracellular milieu and correlates with loss of CFTR-Cl conductance. Although both exon 10 models of CF inhibit acinar apoptosis execution, the ΔF508-CF mouse differs by increasing apoptosis signaling. Impaired transduction of increased apoptosis signaling in ΔF508-CF acini may be biologically relevant to the pathogenesis of AP associated with CFTR mutations. [ABSTRACT FROM AUTHOR]