Bile acids (BAs) are natural end products of cholesterol metabolism (12). The physiological functions of BAs are the emulsification of lipid aggregates and solubilization of lipids in an aqueous environment. The major BAs in humans are chenodeoxycholic acid (CDCA) and cholic acid (CA), which are known as primary BAs since they are synthesized in the liver (46). Before secretion by hepatocytes, primary BAs are conjugated with either taurine or glycine, which increases their polarity and water solubility. Secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA) are produced in the colon by bacterial dehydroxylation of the primary BAs. Under physiological conditions, BAs are temporarily stored in the gallbladder and are released to the intestine. Most of the BAs are then efficiently reabsorbed from the ileum and transported back to the liver via the portal vein (enterohepatic circulation). Under normal, physiological conditions, BAs cannot get into the pancreas. However, under pathophysiological conditions, such as obstruction of the ampulla of Vater by an impacted gallstone, bile can enter into the pancreatic ducts and trigger pancreatitis (32). Unfortunately, we do not know the concentration of bile acids that can reach the pancreatic ductal cells under pathological conditions. It probably varies among patients and mainly depends on the duration of ampullary gallstone obstruction. However, previous studies have shown that relatively low concentrations of BAs (25-200 µM) are able to cause intracellular Ca²⁺ signalling and cell death in acinar cells (23, 49). The close relationship between the passage of a gallstone and the development of acute pancreatitis (AP) has been known for more than a hundred years (32) and has been confirmed in a number of studies (30, 33, 45). However; the pathogenesis underlying the development of biliary AP is not well understood.

Most of the research investigating the pathomechanism of AP has been done on pancreatic acinar cells. These studies have demonstrated that the central intra-acinar events in pancreatitis are elevation of intra-acinar Ca²⁺ concentration, premature activation of trypsinogen and the activation of the proinflammatory transcription factor, nuclear factor-κB (NF-κB) which leads to pancreatic injury (6, 16-18, 36, 44). It has been shown that one of the most toxic BAs to acinar cells is the secondary BA, taurolithocholic acid (TLC) that forms from LCA after re-absorption from the intestine. The sulfated form of TLC (TLCS) causes Ca²⁺ signalling in pancreatic acinar cells via an inositol 1,4,5-trisphosphate (IP₃)-dependent mobilization of sequestered intracellular Ca²⁺  (49). The elevated [Ca²⁺]_i can lead to enzyme activation (36) and/or cell death (23) and result in severe acute necrotizing pancreatitis. Since increased [Ca²⁺] level is a critical step in the initiation of acinar cell injury, several studies have focused on the prevention of cytosolic calcium overload. The calcium chelator, caffeine and its dimethylxanthine metabolites, efficiently decreased TLCS-induced calcium elevation and cell death on isolated pancreatic acinar cells. Caffeine also reduced the severity of TLCS-induced AP, most probably by the inhibition of IP₃R-mediated calcium signalling (20). In another aspect, blocking of Ca²⁺ entry by pharmacological inhibition of store-operated Ca²⁺ channel, Orai-1 has also proven to be effective against the TLCS-induced acinar cell necrosis (52).The target of the sustained Ca²⁺ signal is the Ca²⁺-activated phosphatase, calcineurin, which plays a central role in the intra-acinar activation of zymogens and NF-κB (27). In addition to Ca²⁺, other cellular mechanisms are also involved in the BA-induced acinar injury, such as mitochondrial dysfunction (28, 50), depletion of cytosolic ATP(51) or increased reactive oxygen species (ROS) production (7).

In contrast to acinar cells, the role of pancreatic ductal epithelial cells (PDECs) in the pathogenesis of biliary AP has received much less attention, despite being the first pancreatic cell type exposed to the refluxed bile. Pancreatic ducts can be divided into three main types on the basis of their size and location. These are the main duct, interlobular and intralobular ducts. The main duct mostly collects and drains the juice secreted by other branches of the ductal tree, whereas intra/interlobular ducts are the main sites of HCO₃^- secretion. Although, several studies have shown that ductal fluid and HCO₃^- secretion are crucially important to maintain the integrity of the pancreas (4, 10, 11, 19), the role of PDECs in the development of AP has only been highlighted recently. In vivo studies have shown that pancreatic hypersecretion (with hypoproteinaemia) occurs in the early phase of AP, which develops into hyposecretion during the onset of pancreatitis (10, 11, 19). This hypersecretion may represent a defence mechanism by washing out the toxic factors from the pancreas. The beneficial effect of fluid hypersecretion is further supported by studies in which secretin, one of the major secretagogues of ductal fluid secretion, was shown to reduce the severity of caerulein-induced AP (40, 41). In addition, impaired or insufficient ductal fluid secretion, such as observed in cystic fibrosis, increases the risk of AP (13, 14). Taken together, these data strongly suggest that PDECs represent an important and essential protective mechanism in the exocrine pancreas.

1. Effect of Bile Acids on the Main Pancreatic Duct

In the 1980s, it was postulated that the breakdown of the pancreatic duct permeability barrier is a risk factor for the development of AP. Therefore, researchers extensively investigated the effect of BAs on the morphology and permeability of the main pancreatic duct. In these in vivo studies various BAs were perfused through the cannulated main duct and the permeability of the pancreatic duct mucosal barrier was measured using different techniques (5, 15, 37-39). It has been shown that BAs in high concentrations (2-15 mM), made the ducts permeable to molecules as large as 20,000-daltons, whereas they are normally impermeable to molecules over 3,000-daltons (5, 15). BAs in mM concentrations also increase the permeability of the main duct to Cl^- and HCO₃^- (37-39). The effect of dihydroxy BAs was significantly greater than the effect of trihydroxy BAs on the permeability of these anions, most probably because trihydroxy BAs are less lipid soluble and therefore less toxic to the cells. The changes in ductal permeability were in accord with the changes in the morphology of the ductal epithelia. Perfusion with higher concentrations of BAs (15 mM) caused disruption of cell integrity, flattening of the ductal epithelium and cell loss (5).Due to their detergent properties, this harmful effect of BAs is not surprising.

It was also highlighted that infected bile is more harmful to the duct cells than sterile bile (5, 37, 38). The higher toxicity of infected bile is probably due to bacterial deconjugation, which produces more toxic unconjugated BAs. The toxicity of BAs mainly depends on their solubility and the degree of ionisation. At neutral pH, unconjugated bile acids exist in an unionized (9), electrically neutral, form and therefore can pass easily through the cell membrane. In contrast, glycine- and taurine-conjugated BAs, which have a lower pK_a (around 4 and 2 respectively), are ionized at neutral pH (9) and are therefore less lipid soluble.

Although, in vivo animal studies have a very important significance, their relevance to human disease is doubtful. One of the major problems with these studies is that BAs were used in relatively high concentrations; probably higher than would be present in the pancreatic duct if reflux occurs. Moreover, at these extremely high concentrations, BAs caused excessive and uncontrolled destruction of both acini and ducts.

In vitro studies have allowed the investigation of more pathophysiologically relevant effects of BAs on the ductal epithelium. Okolo et al. studied the effects of BAs (100 µM – 2 mM) on the ion conductances and monolayer resistance of cultured PDECs isolated from the accessory pancreatic duct of dog (31). They found that taurodeoxycholic acid (TDCA) and taurochenodeoxycholic acid caused a concentration-dependent increase in both Cl^- and K⁺ conductances, whereas the trihydroxy BA, taurocholic acid, was completely ineffective. The increases in Cl^- and K⁺ conductances were mediated via elevation of [Ca²⁺]_i and blocked by 4,4^,-diisothiocyanostilbene-2,2^,-disulfonic acid (DIDS) and charybdotoxin, respectively. Using Ussing chambers, they could localize the Cl^- conductance to the apical, and the K⁺ conductance to the basolateral membrane of PDECs. In addition, they showed that only higher concentrations of BAs decreased the monolayer transepithelial resistance. Similar results have been found in bovine PDECs, where TDC markedly increased transepithelial ion transport and decreased the electrical resistance of the tissue (1). On the other hand, TDC caused dose-dependent mucosal damage (2) and at higher concentrations extensive loss of the epithelial cell lining (1).

2. Effect of Bile Acids on the Intra/Interlobular Pancreatic Ducts

Although, the earlier studies described above, characterized the effects of BAs on the permeability and morphology of the main pancreatic duct, no information was available about their effects on the smaller ducts. However, the development of microdissection techniques for the isolation of small intra/interlobular ducts (3), led to a break-through in our understanding of the cellular physiology of the ductal cells.

The major physiological function of the intra/interlobular pancreatic ductal cells is to secrete a HCO₃^--rich alkaline fluid that washes digestive enzymes out of the gland and neutralizes acid chyme in the duodenum (3). The effects of BAs on HCO₃^--secretion have been intensively investigated in the last few years (26, 47, 48), and these studies suggest that the role of ductal cells in the pathomechanism of biliary AP is complex.

Our research group has shown that both basolateral and luminal administration of either non-conjugated or glycine-conjugated forms of CDCA causes a dose-dependent intracellular acidification in guinea pig PDECs (48). Interestingly, basolateral administration of 1 mM CDCA for 6–8 min damaged the membrane integrity, and the cells lost the fluorescent dye, very quickly. The same concentration of CDCA on the luminal membrane had no toxic effects. Okolo et al. also found differences between the effects of BAs on the luminal and basolateral membranes (31). In addition, both CDCA and glycochenodeoxycholate (GCDCA) induced a dose-dependent increase in [Ca²⁺]_i via phospholipase C- and IP₃ receptor-mediated mechanisms. GCDCA had a smaller effect on intracellular pH (pH_i) and (Ca²⁺)_i than CDCA, most probably because conjugated BAs are ionised at neutral pH and therefore require active transport mechanisms for cellular uptake.

We also found that the effect of CDCA on ductal HCO₃^- efflux depends on its concentration (48). At low concentration (0.1 mM), CDCA significantly stimulated HCO₃^- efflux by a DIDS–sensitive Cl^-/HCO₃^- exchange mechanism. The stimulatory effect of CDCA was observed only when CDCA was added to the lumen of the ducts and was dependent on Ca²⁺mobilization. In contrast, high concentration of CDCA (1 mM) caused pathological Ca²⁺ signalling and strongly inhibited HCO₃^- efflux. This inhibitory effect of high concentration of CDCA was independent of changes in [Ca²⁺]_i and was observed when CDCA was applied to either the luminal or the basolateral membrane of the ducts (48). The effect of the conjugated GCDCA on pH_i and [Ca²⁺]_i suggest that although GCDCA can enter the cells, most probably by a transporter-mediated mechanism, it had no effect on HCO₃^-  efflux at both high and low concentrations.

The differences in the effects of low and high concentrations of CDCA suggest that non-conjugated BAs have a specific mode of action on PDECs which strongly depends on their concentration. The key question is the identification of the cellular mechanisms by which BAs exert these opposite effects. Perides et al. have recently identified the presence of a G-protein-coupled bile acid receptor-1 (GPBAR1also known as TGR5) on the apical membrane of acinar cells (34). They showed that GPBAR 1 knockout mice were completely protected against TLCS-induced pancreatitis and suggested that this receptor has a central role in the BA-induced acinar cell injury in mice. In contrast, guinea pig pancreatic ductal cells do not express GPBAR1 (47) suggesting that this receptor is not involved in the effect of CDCA on PDECs.

A) Stimulatory effect of low concentrations of bile acids

Since CDCA only increased HCO₃^- efflux when applied to the luminal membrane, it is likely that the stimulatory effect of CDCA is due to activation of one, or more, Ca²⁺-dependent apical transporters. The SLC26 anion transporters (29, 53) and the Ca²⁺-activated Cl^- channel (CaCC) are known to be activated by an increase in [Ca²⁺]_i suggesting that these transporters could be the target for the CDCA-induced increase in Ca²⁺.

Using the whole cell configuration of the patch clamp technique, CDCA failed to activate CaCC, but induced a robust and reversible increase in K⁺ currents (47). The activated currents could be blocked by the specific large-conductance Ca²⁺-activated K⁺ channel (BK) inhibitor, iberiotoxin. In contrast, the small- and intermediate Ca²⁺-activated K⁺ channel inhibitors, UCL1684 and TRAM34 had no effect on the CDCA-activated currents. Luminal administration of iberiotoxin completely blocked the stimulatory effect of CDCA on HCO₃^- efflux in microperfused ducts. In contrast, basolateral iberiotoxin had no effect on the luminal CDCA-stimulated HCO₃^- efflux. These data strongly indicate that BK channels play a central role in the stimulatory effect of CDCA on HCO₃^- efflux and that they are localized to the luminal membrane of the ductal cells. This latter hypothesis has been confirmed by immunohistochemistry which showed strong expression of BK channels at the apical membrane of guinea pig intra/interlobular ducts (47). Moreover, activation of BK channels by luminal administration of a pharmacological compound, NS11021, increased HCO₃^- efflux in a similar manner to CDCA. Our hypothesis is that activation of apical BK channels leads to the hyperpolarisation of the apical plasma membrane, which in turn increases the electrochemical driving force for anion efflux through SLC26 anion exchangers (Figure 1). The CFTR Cl^- channel is one of the major ion channels on the apical membrane of PDECs, which interacts with the Cl^-/ HCO₃^- exchanger, therefore plays an essential role in HCO₃^- efflux. The possible role of this ion channel has also been raised in the stimulatory effect of CDCA (21). CFPAC-1 is a human, pancreatic ductal cell line which deficient for CFTR, but expresses the SLC26A6 anion exchanger. Administration of 0.1 mM CDCA had no effect on HCO₃^- efflux in these cells. 

Figure 1. Cellular mechanism of the stimulatory effect of CDCA. Low concentration of CDCA (0.1 mM) induces an elevation of (Ca²⁺)_i by two distinct mechanisms: (1) release of (Ca²⁺)_i from the endoplasmic reticulum by an IP₃R- and PLC-mediated pathway and (2) extracellular ATP-induced Ca²⁺ influx directly and indirectly through P2X and P2Y receptors, respectively. The increase in [Ca²⁺]_i  activates BK channels that leads to the hyperpolarisation of the plasma membrane which in turn increases the electrochemical driving force for anion secretion through CFTR and SLC26 anion exchangers. BK: large conductance Ca²⁺-activated K⁺ channel, Ca²⁺: calcium, CDCA: chenodeoxycholic acid, CFTR: cystic fibrosis transmembrane conductance regulator Cl^- channel, Cx: connexin, ER: endoplasmic reticulum, IP₃R: inositol 1,4,5-trisphosphate receptor, Px: pannexin. +: stimulation.

However; after the transduction of CFPAC-1 cells with wild-type CFTR, CDCA significantly stimulated HCO₃^- efflux. CDCA had no effect on the activity of this channel, as demonstrated by the patch clamp technique, although it requires CFTR expression to exert its stimulatory effect (21).

A recent study by Kowal et al. has indicate that in the stimulatory effect of CDCA, release of ATP and activation of purinergic receptors are also involved (24, 25). Using a pancreatic ductal cell line (Capan-1) they showed that CDCA induces a dose-dependent release of ATP which includes both vesicular and non-vesicular mechanism and is more pronounced when CDCA was applied from the luminal membrane. Extracellular ATP than binds to P2 receptors leading to increases in [Ca²⁺]_i which may be involved in the activation of Ca²⁺-activated ion channels, such as BK channels (Figure 1). It has been also shown that Capan-1 cells express GPBAR1 receptor which is activated by CDCA; although activation of this receptor is not involved in the CDCA-induced ATP release.

The stimulatory effect of low concentrations of CDCA highlights the importance of ductal fluid secretion in the protection of the pancreas. The increased volume of fluid can be beneficial in several ways:

(i)            High concentrations of HCO₃^- in the secreted fluid promote the deprotonation of BAs to less toxic bile salts.

(ii)           The increased volume of fluid decreases the concentration of BAs in the ducts.

(iii)          The greater ductal flow may push stones through the papilla of Vater to clear the obstruction.

(iv)         Increased fluid secretion may wash out the toxic BAs from the ductal tree in order to avoid pancreatic injury.

B) Inhibitory effect of high concentrations of bile acids

If the stimulated secretion is not able to wash out BAs from the ductal tree, the luminal concentrations of BAs will increase further. In this situation, high concentrations of CDCA cause pathologic Ca²⁺ signalling and inhibition of the acid/base transporters of PDECs (48). We have provided evidence that mitochondrial damage and depletion of intracellular ATP (ATP_i) are the most crucial factors in the toxic effect of CDCA on pancreatic ductal secretion (26). Administration of 1 mM CDCA to PDECs for 10 minutes caused swelling of the mitochondria and disruption of their inner membranes. Damage of the mitochondria markedly and irreversibly reduced ATP_i. Exposure of pancreatic ducts to carbonyl cyanide m-chlorophenyl hydrazone and deoxyglucose/iodoacetamide (inhibitors of oxidative phosphorylation and the glycolytic pathway respectively) totally mimicked the effect of 1 mM CDCA. These data indicate that CDCA inhibits both the oxidative and glycolytic pathways in PDECs. In addition, it has been shown that ATP_i depletion is crucial in the inhibitory effect of CDCA on ductal ion transport mechanisms. In the absence of ATP_i the acid/base transporters do not work properly, which leads to impaired fluid secretion and finally cell death. (Figure 2) In this case, BAs could reach the acinar cells, either by diffusion up the ductal tree or by leakage into the gland interstitium, where they will switch on pathologic Ca²⁺ signalling and trigger AP. We have also shown that the CDCA-induced mitochondrial injury is due to the opening of mitochondrial permeability transition pore (mPTP), which leads to mitochondrial swelling/dysfunction and consequently inhibition of ATP synthesis (22). Studies on hepatocytes have demonstrated that the toxic effect of hydrophobic BAs can be attenuated by the hydrophilic BA, ursodeoxycholic acid (UDCA) (8, 35, 42, 43). These studies have shown that the cytoprotective effect of UDCA is largely based on its ability to stabilize the mitochondrial membrane by the inhibition of BA-induced mPTP opening. 24 h pre-treatment of the pancreatic ducts with 0.5 mM UDCA significantly decreased the CDCA-induced mitochondrial injury by the inhibition of CDCA-induced mPTP and ATP_i loss and reduced the inhibitory effect of CDCA on the acid/base transporters (22). Moreover, the protective effect of UDCA on the mitochondria is associated with anti-apoptotic effect which raises the possible therapeutic use of UDCA in the treatment of bile-induced AP.

3. Conclusion

Taken together, both in vivo and in vitro studies indicate that once BAs reach the ductal epithelium, depending on their concentration, they exert a harmful or beneficial effect on PDECs (Table 1). This biphasic effect of BAs on ductal secretion may be a significant factor in the pathomechanism of biliary AP. 

Figure 2. Cellular mechanism of the inhibitory effect of CDCA. High concentration of CDCA (1 mM) induces toxic (Ca²⁺)_i signal, mitochondrial damage and depletion of ATP_i that leads to the inhibition of acid-base transporters of PDEC. 24 h pre-treatment of the ducts with UDCA (0.5 mM) is able to prevent the toxic effect of CDCA by the stabilization of the mitochondrial membrane.  BK: large conductance Ca²⁺-activated K⁺ channel, Ca²⁺: calcium, CDCA: chenodeoxycholic acid, CFTR: cystic fibrosis transmembrane conductance regulator Cl^- channel, Cx: connexin, ER: endoplasmic reticulum, IP₃R: inositol 1,4,5-trisphosphate receptor, Px: pannexin, UDCA: ursodeoxycholic acid. -: inhibition.

Table 1. Summary of the effect of bile acids on pancreatic ductal epithelial cells. CA: cholic acid, CDCA: chenodeoxycholic acid, DCA: deoxycholic acid, GCA: glycocholic acid, GDCA: glycodeoxycholic acid, GCDCA: glycochenodeoxycholic acid, TCA: taurocholic acid, TCDCA: taurochenodeoxycholic acid, TDCA: taurodeoxycholic acid.

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