Bile and pancreatic juice exclusion activates acinar stress kinases and exacerbates gallstone pancreatitis

Abstract

Bile and pancreatic juice exclusion from gut activates acinar stress kinases and exacerbates gallstone pancreatitis as evidenced by the ameliorating effects of replacement therapy in an experimental model of duct ligation-induced acute pancreatitis. In the early stages of gallstone pancreatitis, bile-pancreatic juice cannot enter the gut. Enteral exclusion worsens pancreatitis by causing feedback hyperstimulation of the exocrine pancreas that activates acinar cell stress kinases. Investigations using a unique surgical model, the Donor Rat Model, showed that duodenal replacement of bile-pancreatic juice in rats with duct ligation attenuates pancreatic stress kinase activation, reduces pancreatic cytokine production, and ameliorates pancreatic morphologic changes. These findings suggest that exclusion-induced acinar hyperstimulation, in the presence of duct obstruction, exacerbates acute pancreatitis via stress kinase activation. Although acinar hyperstimulation has often been implicated in the pathogenesis of acute pancreatitis, the lack of supporting evidence remains a conspicuous void. The proposed hypothesis draws on fresh evidence to present a new paradigm that reexamines the role of exocrine pancreatic hyperstimulation in gallstone pancreatitis pathogenesis.

Figure 1. Hyperstimulation against obstruction

A car engine over-heated from forceful acceleration against an unyielding garage door illustrates acinar cell stress from hyperstimulation in the presence of an obstructed duct. In this diagrammatic representation of acinar hyperstimulation in gallstone pancreatitis, the engine going up in flames exemplifies acute inflammation of the pancreas.

Figure 2. The Donor Rat Model

Each donor rat was prepared with a bile-pancreatic fistula and a duodenal fistula, allowing external diversion and duodenal re-circulation of bile and pancreatic juice. Enteral feeding was instituted via a gastric fistula during a three-day post-laparotomy recovery period. When experiments were begun, bile and pancreatic juice were donated to an experimental (recipient) rat via a duodenal fistula beginning immediately before duct ligation. In an additional set of donor rats, a separate bile fistula and pancreatic juice fistula was created allowing experimental rats with duct ligation to receive either bile replacement alone or pancreatic juice replacement alone (not shown here).

Figure 3. Paradigm of sequential biological interactions

This is a diagrammatic representation of a paradigm for early events in the pathogenesis of duct ligation-induced acute pancreatitis in rats. Three sequential biological interactions (circled numbers) involving hyperstimulation delineate salient extracellular events that affect the pancreatic acinar cell environment in the rat model: 1) A synergistic interaction between pancreatic juice exclusion and bile exclusion augments the neuro-hormonal duodenal response to bile-pancreatic juice exclusion, 2) An interaction between CCK-A receptor stimulation and cholinergic (ACh) muscarinic receptor stimulation further increases acinar hyperstimulation, and 3) An interaction between acinar hyperstimulation and duct obstruction (“No Entry” sign) imposes excess stress on the acinar cell, activating stress kinases that induce production of acute inflammatory mediators.