John K. Stevenson

Inhibition of Prostaglandin Synthesis Fails to Prevent Gallbladder Mucin Hypersecretion in the Cholesterol-Fed Prairie Dog

Gallstone formation in the cholesterol-fed prairie dog is preceded by an increase in mucin secretion by the gallbladder epithelium, and mucin hypersecretion is believed to promote cholesterol gallstone formation by accelerating the nucleation of cholesterol monohydrate crystals. Some studies have suggested that gallbladder mucin hypersecretion is mediated by increases in gallbladder prostaglandin synthesis, but other observations are difficult to reconcile with this view. An organ culture technique was used to measure mucin secretion in normal prairie dog gallbladder in response to exogenous prostaglandins and agents that increased or decreased endogenous prostaglandin production. Incubation with indomethacin produced a concentration-dependent inhibition of endogenous prostaglandin synthesis with virtually complete inhibition at 10(-5) mol/L indomethacin. However, indomethacin had no effect on gallbladder mucin secretion at concentrations as high as 10(-5) mol/L, and significant inhibition of mucin secretion was only found at 10(-4) mol/L indomethacin, a concentration that also produced a significant increase in lactate dehydrogenase release from cultured explants. Incubation of gallbladder explants with the calcium ionophore A23187 significantly stimulated endogenous prostaglandin synthesis in a concentration-dependent manner, increasing synthesis of prostaglandins E and F to as much as 278% +/- 20% and 335% +/- 21% of basal values, respectively; however, the same concentrations of A23187 did not stimulate mucin secretion. Incubation of gallbladder explants in the presence of exogenous prostaglandin E2 or prostaglandin F2a in concentrations as high as 10(-6) mol/L also did not stimulate mucin secretion. Prairie dogs fed a lithogenic 1.2% cholesterol diet showed a significant increase in gallbladder mucin secretion after 1 week (117.5 +/- 10.2% of control, P less than 0.05), and 4 of 5 had formed cholesterol monohydrate crystals after 3 weeks. Long-term treatment with indomethacin, 1.2 mg.kg-1.day-1, failed to inhibit gallbladder mucin hypersecretion (129.2 +/- 10.7% of control after 1 week) or cholesterol monohydrate crystal formation (3/5) in cholesterol-fed prairie dogs. Furthermore, incubation of explants with 10(-5) mol/L indomethacin failed to prevent in vitro mucin hypersecretion in cholesterol-fed animals. These findings suggest that prostaglandins do not regulate gallbladder mucin secretion in the prairie dog, and it is unlikely that increases in gallbladder prostaglandin synthesis are responsible for mediating gallbladder mucin hypersecretion during cholelithiasis in the prairie dog.

The behavior of foreign bodies (imitated “gallstones”) in the extrahepatic biliary system

Abstract A method has been demonstrated herein which allows for investigating the extrahepatic biliary system by injecting contrast material directly into the biliary tree, thereby achieving films similar in quality to an operative cholangiogram, but without the necessity of an exploration. Various sizes of stainless steel ball bearings, simulating gallstones, were inserted into the gallbladder. The passage of these “stones” was followed by radiography. After the complete disappearance of the ball bearings (19 to 124 days) the animals were sacrificed and the extrahepatic biliary system was histologically examined. It was noted that the duct system dilated during the passage of these foreign bodies.