Gallbladder (GB) mucus hypersecretion plays a critical role in gallstone pathogenesis by accelerating nucleation and precipitation of cholesterol-supersaturated bile. We have shown that GB mucus hypersecretion is probably mediated by prostaglandins (PGs) and/or lysophosphatidylcholine (LPC), which are generated by the GB at abnormally high rates in the prairie dog on a lithogenic diet. These increases in PG synthesis and LPC production precede mucus hypersecretion and stone formation. Our hypothesis is that increases in gallbladder PGs and LPC in early stone pathogenesis result from increased phospholipase A2 activity in GB mucosa. Furthermore, GPs and LPC STIMULATE GB mucus secretion and thus promote nucleation of cholesterol- supersaturated bile. In this study we will validate assays for mucosal phospholipase A2 in the prairie dog. These assays will be used to determine whether increases in GB PG synthesis and LPC concentration in early cholelithiasis are mediated by increased phospholipase activity in GB mucosa. Phospholipase activity will be measured in GB, stomach and ileal mucosa from prairie dogs fed either a control (trace cholesterol) or lithogenic (0.34% cholesterol) diet for periods of 1, 2, 4, 6, or 8 weeks. Mucosal samples will also be used to measure PG synthesis using previously validated methods. Mucin, LPC, and biliary lipid concentrations will be measured in GB and hepatic bile. The temporal relationships among changes in these parameters will suggest their role in cholesterol cholelithiasis, and subsequent studies in which control and cholesterol-fed prairies dogs are treated with varying doses of a phospholipase A2 inhibitor will further establish these relationships. Finally, we will use HPLC to measure the molecular species of phospholipids in bile and mucosal samples in order to establish the presence or absence of diet-induced alterations in phospholipids which could potentially contribute to the increases in gallbladder PGs and LPC noted by us in this model.
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|Chapman, W C; Peterkin 3rd, G A; LaMorte, W W et al. (1989) Alterations in biliary motility correlate with increased gallbladder prostaglandin synthesis in early cholelithiasis in prairie dog. Dig Dis Sci 34:1420-4|
|Booker, M L; Scott, T E; La Morte, W W (1989) Effect of dietary cholesterol on phosphatidylcholines and phosphatidylethanolamines in bile and gallbladder mucosa in the prairie dog. Gastroenterology 97:1261-7|