EFFECTS OF LONG-TERM URSODEOXYCHOLATE ADMINISTRATION ON EXPRESSION LEVELS OF SECRETORY LOW-MOLECULAR-WEIGHT PHOSPHOLIPASES A(2) AND MUCIN GENES IN GALLBLADDERS AND BILIARY COMPOSITION IN PATIENTS WITH MULTIPLECHOLESTEROL STONES

Group IIA phospholipase A(2) (PLA(2)), a secretory low-molecular-weigh t PLA(2), may play a critical role in the process of gallbladder mucos al inflammation in multiple cholesterol stones, which in turn may prod uce biliary pronucleating proteins as well as mucin, On the other hand , ursodeoxycholate (UDC) decreases biliary levels of various pronuclea ting proteins, possibly because of its membrane-protective effects on the inflamed gallbladder mucosa. To elucidate that beneficial effect o f UDC, the expression levels of low-molecular-weight PLA(2)s, group II A PLA(2) (PLA(2)-IIA), and group V PLA(2) (PLA(2)-V), and mucin core p olypeptide genes in the gallbladders were studied for UDC-treated pati ents and untreated patients with multiple cholesterol stones, Furtherm ore, the results were correlated with alterations in biliary compositi on. With long-term administration of UDC, the PLA(2)-IIA protein mass (2.7 +/- 0.5 vs. 5.0 +/- 0.4 ng/mg protein [mean +/- SEM]; P < .01) an d steady-state mRNA level, as well as the PLA(2)-V mRNA. level, were s ignificantly decreased in the gallbladders, where the prostaglandin E- 2 (PGE(2)) level was concomitantly decreased (190.7 +/- 27.9 vs. 393.6 +/- 55.3 pg/mg protein; P < .01), In the gallbladder bile, the immuno radiometrically determined PLA(2)-IIA levels were significantly decrea sed in the UDC-treated patients (43 +/- 4 ng/dL; P < .01) in compariso n with untreated patients (78 +/- ng/dL). Significant decreases were s imilarly found for total protein, mucin, and free arachidonate concent rations, as well as nucleation activity in the bile. The degree of the changes was found to be rather small in solitary stones. In contrast to the decreased mucin concentration, however, there were no significa nt changes in the expression levels of mucin core polypeptide genes (M UC1-MUC6) between the UDC-treated and untreated patients. Long-term UD C administration was observed to lower the increased PLA(2)-IIA protei n mass and mRNA level, as well as the PLA(2)-V mRNA level, in the gall bladders of patients with multiple cholesterol stones, which in turn m ay be of therapeutic importance in improving the gallbladder mucosal i nflammation. Effects of UDC on secretory low-molecular-weight PLA(2)s as inflammatory mediators may relate to the reported efficacy of UDC t reatment in cholesterol gallstone disease.