The Role of Cystic Fibrosis Transmembrane Conductance Regulator Cl Channel in Pancreatitis

Excessive alcohol consumption is a major cause ofacute pancreatitis, but the mechanism involved is not wellunderstood. Recent investigations suggest that pancreatic ductalepithelial cells (PDECs) help defend the pancreas from noxiousagents such as alcohol. Because the cystic fibrosis transmem-brane conductance regulator (CFTR) Cl channel plays a majorrole in PDEC physiology andmutated CFTR is often associatedwith pancreatitis, we tested the hypothesis that ethanol affectsCFTR to impair ductal function. Electrophysiological studieson native PDECs showed that ethanol (10 and 100 mM) in-creased basal, but reversibly blocked, forskolin-stimulatedCFTR currents. The inhibitory effect of ethanol was mimickedby its non-oxidative metabolites, palmitoleic acid ethyl ester(POAEE) and palmitoleic acid (POA), but not by the oxidativemetabolite, acetaldehyde. Ethanol, POAEE and POAmarkedlyreduced intracellular ATP (ATPi) which was linked to CFTRinhibition since the inhibitory effects were almost completelyabolished if ATPi depletion was prevented. We propose thatethanol causes functional damage of CFTR through an ATPi-dependent mechanism, which compromises ductal fluid secre-tion and likely contributes to the pathogenesis of acute pancre-atitis. We suggest that the maintenance of ATPi may represent atherapeutic option in the treatment of the disease.