ANTICHOLESTATIC MECHANISMS OF URSODESOXYCHOLIC ACID IN INFLAMATORY CHOLESTASIS INDUCED BY LIPOPOLYSACCHARIDE (LPS)

RAZORI MV; RUIZ ML; MAIDAGAN MP; ROMA MG; ANDERMATTEN RB

Mar del Plata

Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2016

Backgrouds and aims: Sepsis-induced cholestasis is causally associated with the release of LPS from Gram (-) bacteria; LPS stimulates the production of proinflammatory cytokines which, in turn, impair expression/localization of key transporters involved in bile formation, such as Bsep and Mrp2. Ursodeoxycholic acid (UDCA) is the first choice therapy for cholestatic diseases, but its therapeutic efficacy in LPS-induced cholestasis is unknown. Therefore, we will study its therapeutic mechanisms here.Methodology: Male Wistar rats were randomized in 4 experimental groups: Control, UDCA (25 mg/Kg/day, i.p., 5 days), LPS (total dose of 10 mg/Kg, i.p., over the last 2 days), and UDCA+LPS. On the 6th day, serum alkaline phosphatase (ALP, an hepatic enzyme removed by detergent bile salts (BS) accumulated in cholestasis), bile flow (BF), bile salt output (BSO), total glutathione output (GSHtO), and total/plasma membrane liver protein expression of canalicular transporters were assessed.Results (% of control): Pretreatment of LPS-treated rats with UDCA reduced serum ALP as compared with LPS alone (193±14*# vs. 254±15*), and increased BSO (85±20*# vs. 57±10*), a finding in line with the increased proportion of Bsep in plasma membrane (94±38*# vs. 39±11*). LPS reduced BF (79±3*), GSHtO (47±7*), and the protein levels of Bsep (41±11*) and Mrp2 (39±20*) in whole liver homogenate, but UDCA failed to improve these parameters (*p