Fluid and ion transport across biliary epithelium contributes to bile flow. Alterations of this function may explain hepatobiliary complications in cystic fibrosis (CF). We investigated electrogenic anion transport across intact non-CF and CF human gallbladder mucosa in Ussing-type chambers. In non-CF tissues, baseline transmural potential difference (PD), short-circuit current (Isc), and resistance (R) were ؊2.2 ؎ 0.3 mV (lumen negative), 40.7 ؎ 7.8 A/cm 2 , and 66.5 ؎ 9.6 ⍀ · cm 2 , respectively (n ؍ 14). The addition of forskolin (10 ؊5 mol/L) to the apical and basolateral baths and that of adenosine 5Ј-triphosphate (ATP) (10 ؊4 mol/L) to the apical bath induced significant increases in Isc by 8.0 ؎ 1.4 and 10.3 ؎ 1.8 A/cm 2 , respectively. Depletion of bathing solutions in Cl ؊ and HCO 3 ؊ significantly reduced baseline Isc and the forskolin-and ATPinduced increases in Isc. Anion secretion was stimulated by extracellular ATP via P2Y 2 purinoceptors, as indicated by the effects of different nucleotides on Isc and on 36 Cl efflux in cultured gallbladder epithelial cells. This effect was mediated by cytosolic calcium increase and Ca 2؉ /calmodulindependent protein kinase II, as ascertained by using inhibitors. In CF preparations, basal PD and Isc were lower than in non-CF, and the response to forskolin was abolished, whereas the response to ATP was enhanced (P F .05 for all). We conclude that electrogenic anion secretion occurs in human gallbladder mucosa under basal state and is stimulated by an adenosine 3Ј,5Ј-cyclic monophosphate (cAMP)-dependent pathway mediated by cystic fibrosis transmembrane conductance regulator (CFTR), and by exogenous ATP via a CFTR-independent pathway that is up-regulated in CF and involves P2Y 2 purinoceptors and a calciumdependent pathway. (HEPATOLOGY 1999;29:5-13.)
Whether bile acids regulate biliary epithelial cell (BEC) secretory functions in human is poorly known. The purpose of the study was to determine if human gallbladder-derived BEC exhibit bile acid transport activity that affect their secretory functions and to evaluate the influence of bile acid hydrophobicity in this response by comparing the effects of tauroursodeoxycholate (TUDC) and of taurochenodeoxycholate (TCDC). Expression of the apical sodium-dependent bile acid transporter (ASBT) and of the organic anion transporting polypeptide (OATP-A) was detected and associated with sodium-dependent and sodium-independent [ 3 H]taurocholate uptake in BEC. Sodium-dependent uptake (K m , 66 ؎ 2.5 mol/L; Vmax, 39.4 ؎ 4.6 pmol/mg protein/ min) was significantly higher than sodium-independent uptake. TCDC stimulated Cl ؊ efflux and mucin secretion in cultured cells, and both effects were sodium-dependent. Both TCDC and TUDC were efficiently transported in BEC, as assessed by competitive uptake experiments. However, as compared with TCDC, TUDC induced significantly lower mucin secretion whereas there was no significant difference between TCDC-and TUDC-induced chloride efflux. Protein kinase C down-regulation caused a 70% reduction in TUDCinduced mucin secretion, but did not affect TCDC-induced secretion, which was mediated predominantly by Ca 2؉ /calmodulin-dependent protein kinase II activation. These results provide evidence that bile acids may be transported mainly via ASBT in human gallbladder BEC and stimulate hydroelectrolytic and mucin secretion in these cells. Individual bile acids activate different signaling pathways leading to a different balance between mucin and chloride secretion. The differential effect of TUDC may cause a reduction in bile inspissation and provide a benefit in biliary disorders. (HEPATOLOGY 2001;33:496-503.)
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