Introduction: Using a unique surgical model (The Donor Rat Model), we previously showed that duodenal replacement of bile-pancreatic juice, obtained fresh from a donor rat, ameliorates pancreatic morphologic changes and hypercholecystokininemia in ligation-induced acute pancreatitis. We hypothesize that bile-pancreatic juice exclusion from gut exacerbates activation of the pro-inflammatory Akt/NF-kappaB pathway and induces chemokine production in ligation-induced acute pancreatitis. The cytosolic I-kappaB/NF-kappaB complex dissociates when I-kappaB is phosphorylated by activated Akt, allowing NF-kappaB to translocate to the nucleus and promote transcriptional upregulation of various inflammatory mediators including chemokines.
Methods:We studied 36 rats as follows: Diseased-controls had bile-pancreatic duct ligation. Diseased-treated rats had duodenal bile-pancreatic juice replacement fresh from a Donor Rat beginning immediately before duct ligation. Sham-operated controls had ducts dissected only. Rats were killed after 1 or 3h (n=6/group). Pancreatic homogenates were used to determine Akt activation (immunoblotting, immune complex kinase assay and ELISA), I-kappaB activation (immunoblotting), and production of chemokines MCP-1 and RANTES (ELISA). NF-kappaB was quantitated in nuclear fractions using Electro-Mobility Shift Assay (EMSA). Results: Compared to sham, duct ligation was associated with significant increases in pancreatic Akt activation, I-kappaB activation, NF-kappaB activation and nuclear translocation, and MCP-1 and RANTES production. Activation of the Akt/NF-kappaB pathway and increased MCP-1 and RANTES production after duct ligation were substantially ameliorated by bile-pancreatic juice replacement (ANOVA, p<0.05). Conclusion: Bile-pancreatic juice exclusion from gut exacerbates Akt/NF-kappaB pathway activation and increases chemokine production in ligation-induced acute pancreatitis. These findings support our central hypothesis that bile-pancreatic juice exclusion from gut activates pro-inflammatory signal transduction pathways and exacerbates acute pancreatic inflammation in this experimental corollary of gallstone-induced acute pancreatitis. Our Donor Rat Model provides a unique opportunity to study the role of the enteral response to bile-pancreatic juice exclusion in the mechanisms of disease pathogenesis. (Support: American College of Surgeons Faculty Research Fellowship; NIH Career Development Award #K08-DK062805.)
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