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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-.

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Nerve Regulation of Cholangiocyte Functions

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Cholangiocytes are epithelial cells that line the intrahepatic biliary tree, a three-dimensional network of interconnecting ducts of different sizes and functions. The objectives of this chapter are to review the recent findings related to the role of nerves in the regulation of cholangiocyte functions. Following an overview of the morphology of the biliary epithelium, we provide a brief summary of cholangiocyte functions followed by a description of the in vivo models and the in vitro experimental tools [e.g., purified cholangiocytes or isolated intrahepatic bile duct units (IBDU)] that allowed us to demonstrate the role of nerves in the regulation of cholangiocyte functions. Following a discussion on the receptors/transporters that are expressed by cholangiocytes, we discuss the role of cholinergic, adrenergic and dopaminergic nerves in the regulation of cholangiocyte pathophysiology. The role of other neurotransmitters (e.g., bombesin and vasoactive intestinal peptide) on cholangiocyte functions is not covered here, as it is discussed in another chapter.

Anatomical and Morphological Features of the Biliary Epithelium

The biliary epithelium is divided into three different sized segments that include the extrahepatic bile duct, large bile ducts and intrahepatic small bile ducts.1-4 The bile duct system extends from the canals of Hering to the large extrahepatic ducts.1-4 In humans, the intrahepatic biliary epithelium has been divided based upon duct size:2,3 small bile ductules (<15 micrometers in diameter), interlobular ducts (15-100 micrometers in diameter), septal ducts (100-300 micrometers in diameter), area ducts (300-400 micrometers in diameter), segmental ducts (400-800 micrometers in diameter) and hepatic ducts (> 800 micrometers in diameter).2,3 Based upon morphological, phenotypic and functional differences among ducts of different diameter,1,2,5,6 we have recently classified the intrahepatic bile duct system into small (< 15 micrometers in diameter) and large (> 15 micrometers in diameter) ducts.1,2,5,6

Small ductules are lined by 4-5 cholangiocytes and are characterized by the presence of a basement membrane, tight junctions between cells and microvilli projecting into the bile duct lumen.4,7 Small bile ducts join into interlobular ducts ranging from 20-100 micrometers in cross-sectional diameter.3,4,7 Cholangiocytes are progressively larger and more columnar in shape in larger bile ducts.3,4,7

Experimental in Vivo and in Vitro Models for Studying the Role of Nerves in the Regulation of Cholangiocyte Functions

Growing information related to the role of nerves in the regulation of cholangiocyte functions came from the development of in vivo experimental models and tools.2,5,6,8-15 The bile duct ligation (BDL) is a rat model that induces an increase in the number of intrahepatic bile ducts1,8,9,11,14 and has helped us in the generation of novel information on the role of nerves in the regulation of cholangiocyte proliferation, apoptosis and secretion.1,13,16-23 The BDL rat is an hyperplastic model with a marked increase in secretin-stimulated choleresis,8 which is absent in normal rats.8 The increase in ductal secretion in the BDL rat is due to an increased number of secreting ducts8 and enhanced responsiveness of cholangiocytes to secretin due to up-regulation of the secretin receptor.24

The isolation of pure cholangiocytes and IBDU from normal and BDL rats has allowed us to have a better understanding of the role of cholinergic,16,19,23 adrenergic18,20,21 and dopaminergic13,17 innervation in the regulation of cholangiocyte proliferation, apoptosis and secretion.13,16-21,23

Brief Overview of Cholangiocyte Functions

The secretion of bile by the liver depends upon functional interactions between hepatocytes and cholangiocytes.1,8 Transport of bile salts, glutathione, lipids, proteins and other organic solutes into the canalicular space between the hepatocytes generates an osmotic gradient favoring influx of water.25 Cholangiocytes determine the fluidity and alkalinity of canalicular bile by a series of reabsorptive and secretory events that leads to the final composition of bile.8 Ductal secretion contributes up to approximately 10% of total bile flow in human and 30% in rats.1,9 Ductal secretion is coordinately regulated by gastrointestinal hormones,1,5,6,8-11,24,26-28 peptides,29 bile salts,30,31 enzymes (e.g., alkaline phosphatase)12 and nerves.13,14,16,17,19-11,23,32 Secretin stimulates ductal secretion1,5,6,8-11,32 by selective interaction with secretin receptors expressed only by cholangiocytes in rat liver.24 The interaction of secretin with its own receptor24 leads to an increase in intracellular cAMP levels,1,5,6,10,11,32 activation of PKA,33 opening of CFTR Cl- channels34 with activation of the Cl-/HCO3 - exchangers,1,5,6,16,33 which leads to secretion of bicarbonate into bile.8 Other gastrointestinal hormones regulate ductal bile secretion.11,14,32,35 Somatostatin inhibits basal and secretin-stimulated ductal secretion interacting with SSTR2 somatostatin receptors by decreasing intracellular cAMP levels.11,35 Gastrin decreases secretin-stimulated ductal secretion and cAMP levels interacting with CCK-B (but not CCK-A) receptors by activation and membrane translocation of PKC alpha.14,32

Cholangiocytes are the target cells in a number of human diseases affecting the biliary tree (cholangiopathies) including primary biliary cirrhosis and primary sclerosing cholangitis, which are characterized by cholangiocyte proliferation/loss.1,36 In animal models, cholangiocyte proliferation/loss is obtained by a number of maneuvers such as Bile Duct Ligation (BDL),8,11,14 alpha-naphthylisothiocyanate (ANIT)9,37 or bile salt feeding,31 acute administration of carbon tetrachloride38,39 or partial hepatectomy.15 Interestingly, in a fashion similar to what is shown in human cholangiopathies,40,41 in rat models, cholangiocyte proliferation/loss is associated with changes in secretin-regulated ductal secretion.1,8,9,11,14,15,19,24,31,32,37-39 Following partial hepatectomy or chronic feeding of bile salts or ANIT, there is an increase in the response of intrahepatic bile ducts to secretin by increased secretin receptor expression and secretin-stimulated cAMP levels.9,37-39 Moreover, ductopenia induced by acute administration of carbon tetrachloride, is associated with decreased secretory activity of large secretin-responsive ducts. The classical model of ductal hyperplasia, the BDL rat, is commonly used for evaluating the changes in cholangiocyte proliferation, apoptosis and secretion. The data related to the role of nerves in the regulation of cholangiocyte functions, which are described in this chapter, have been mostly obtained in the BDL rat model. The rationale for using this model is based on: (i) secretin does not increase choleresis in normal rats;8,15,32 (ii) following BDL there is a marked increase in ductal secretion,8,32,35 which allows for better evaluation of the changes in basal and secretin-stimulated cholangiocyte secretion; and (iii) cholangiocytes from BDL rats retain normal phenotypes of biliary lineage.42

Innervation of the Liver

Sympathetic and parasympathetic nerves within the liver are located around the hepatic artery, portal vein, and intrahepatic and extrahepatic bile ducts.43,44 These nerves originate from the celiac ganglion (sympathetic) and from the vagus nerve (parasympathetic).43,44 The intrahepatic arteries, veins, bile ducts and hepatocytes are innervated.43,44 In many autonomic nerves there are, within the classical neurotransmitters, regulatory peptides such as neuropeptide tyrosine (NPY) and its C-flanking neuropeptide C-PON, (mainly found in sympathetic adrenergic fibers,45,46 calcitonin gene related peptide (CGRP), somatostatin, vasoactive intestinal polypeptide (VIP) (mostly associated with parasympathetic cholinergic fibers), enkephalin and bombesin.46-50 NPY-positive nerves have been identified in extrahepatic bile ducts51 and have direct vasoconstrictor properties, suggesting an endocrine-paracrine control of bile flow.52 In guinea pig and rat liver, nerve fibers containing the regulatory peptides CGRP and substance P are present around blood vessels and bile duct radicles within portal tracts, but are not detectable around the sinusoids.53,54 VIP-positive nerve fibers are located in the walls of hepatic arteries, portal veins and bile ducts.55 Physiological and pharmacological studies have indicated that the motor (efferent) innervation plays an important roles in intrahepatic hemodynamic and bile flow regulation,56-59 and parenchymal cell regeneration,60 whereas the sensory (afferent) supply may be involved in osmoreception, ionoreception, baroreception and in the control of hepatic metabolic receptors.61-66

Cholinergic Regulation of Cholangiocyte Functions

The cholinergic system regulates gastrointestinal physiology through the modulation of vascular, metabolic and secretory events as well as motility by interaction with specific muscarinic receptor subtypes (M1-M5). Five distinct but related muscarinic genes (M1-M5) have been demonstrated recently by molecular cloning studies, but the expressed product of the M5 receptor gene does not yet have an equivalent functional pharmacological profile nor a defined tissue localization. From a functional point of view, M1, M3, and M5 are preferentially coupled to hydrolysis of phosphoinositide, while M2 and M4 are linked to the inhibition of the adenylyl cyclase activity.67-71 A number of studies showed that cholinergic nerves regulate bile secretion in liver.72-75 In bile—fistula dogs with interrupted enterohepatic circulation, distal stimulation of the vagus nerve increases bile bicarbonate secretion, whereas vagotomy decreases basal bile flow and bicarbonate output;72,73 in anaesthetized sheep,74 vagal electrical stimulation enhances bicarbonate biliary secretion without significant changes in bile flow. Insulin regulation of bile flow is thought to be mediated by cholinergic nerves.75

Recent studies have shown22,76 that: (i) impure isolated rat cholangiocytes and the human cholangiocarcinoma cell line, Mz-ChA-1, express the M1 and M3 acetylcholine (ACh) receptor subtypes; and (ii) the cholinergic agonist, carbachol, stimulates bile flow of the isolated perfused rat liver through an increase in free cytosolic Ca2+ level. Consistent with the concept that cholangiocytes but not hepatocytes express ACh receptors, other studies showed that ACh does not affect the functions of hepatocytes, but elicits Ca2+ increase and oscillation in isolated bile duct units (IBDU), due to both an influx of extracellular Ca2+ and the mobilization of thapsigargin-sensitive Ca2+ stores.23 In contrast to the studies by Elsing et al,22,76 recent studies by Alvaro et al have shown16 that cholangiocytes express, at the basolateral domain, M3 (but not M1 and M2) Ach receptors (fig. 1). The study shows that ACh has no effect on the basal activity of the Cl-/HCO3- exchanger, but it significantly potentiates the stimulatory effect of secretin on these anions exchanger (fig. 2).16 ACh-regulation of bicarbonate secretion from bile ducts takes place during the digestive phase when the parasympathetic system predominates and secretin targets large bile ducts.16 In this phase the bicarbonate requirement in the intestine is maximal. By selectively interacting with M3 receptor subtypes, ACh induces a Ca2+-calcineurin mediated potentiation of the secretin-induced adenylyl cyclase activity, which leads to activation of the Cl-/HCO3- exchanger with bicarbonate secretion into bile.16 Furthermore, recent studies have shown that ACh sustains cholangiocyte proliferation, since interruption of the cholinergic innervation by vagotomy induces a marked decrease in total bile duct mass caused by both impaired cholangiocyte proliferative capacity (fig. 3) and intracellular cAMP levels (fig. 4), and enhanced cell death by apoptosis.19 The decrease in the number of intrahepatic bile ducts is associated with decreased basal and secretin-stimulated cAMP levels, which leads to inhibition of ductal secretory activity.16 The studies also show that maintenance of intracellular cAMP levels (by chronic administration of forskolin) prevents the effects of vagotomy on cholangiocyte apoptosis, proliferation and secretion (fig. 4).16 Moreover, recent studies have shown77 that chronic taurocholate feeding prevents vagotomy effects on cholangiocyte functions by stimulation of the PI3-kinase/Akt pro-survival pathway. The data suggests that bile salts may directly interact with M3 ACh receptors, thus regulating in concert with nerves the balance between cholangiocyte proliferation/loss in cholangiopathies. In support of this novel concept, recent preliminary data showed that interaction of bile acids (e.g., lithocholyltaurine and deoxycholylglycine) with M3 ACh receptors stimulates colon cancer cell proliferation by inducing p90RSK phosphorylation via a calcium-, MEK- and MAPK-dependent pathways.78

Figure 1. Immunofluorescence of IBDU isolated from rat liver and exposed to muscarinic ACh receptor monoclonal antibody (M35).

Figure 1

Immunofluorescence of IBDU isolated from rat liver and exposed to muscarinic ACh receptor monoclonal antibody (M35). Fluorescent signal was preferentially localized at the basolateral area of the biliary epithelium (arrowheads). Orig. magn., x 60.

Figure 2. Effect of ACh on basal and secretin-stimulated Cl-/HCO3- exchanger activity in IBDU.

Figure 2

Effect of ACh on basal and secretin-stimulated Cl-/HCO3- exchanger activity in IBDU. The Cl-/HCO3- exchanger activity was evaluated by measuring the maximal rate of alkalinization after Cl- removal (equimolar substitution with gluconate) and the maximal (more...)

Figure 3. Immunohistochemistry for CK-19 in frozen liver sections (n=6) from BDL (A) and BDL+vagotomy (B) rats.

Figure 3

Immunohistochemistry for CK-19 in frozen liver sections (n=6) from BDL (A) and BDL+vagotomy (B) rats. Note that vagotomy induced a marked decrease in the number of ducts as compared with BDL control rats. Orig. magn., x125.

Figure 4. A) Measurement of basal and secretin-induced cAMP levels in cholangiocytes from BDL or BDL+vagotomy rats.

Figure 4

A) Measurement of basal and secretin-induced cAMP levels in cholangiocytes from BDL or BDL+vagotomy rats. *p < 0.05 vs. basal cAMP levels of cholangiocytes from BDL rats. **p < 0.05 vs. secretin-induced cAMP levels of cholangiocytes from (more...)

Adrenergic and Dopaminergic Regulation of Cholangiocyte Functions

There is growing information regarding the role of adrenergic and dopaminergic innervation in the regulation of cholangiocyte proliferation and secretion.20 An intact sympathetic innervation is required for hepatocyte and cholangiocyte proliferation following partial hepatectomy.79 Recent studies have shown that: (i) cholangiocytes from BDL rats express alpha-1, alpha-2, beta-1 and beta-2 adrenergic receptors; and (ii) alpha-1 (but not beta-1) adrenergic receptor agonists increase secretin-stimulated ductal secretion by Ca2+-, and PKC-dependent mechanisms.20 Similar to what is shown in the gut, adrenergic innervation may play a role in counterbalancing the stimulatory effects of cholinergic nerves19 on ductal bile secretion in chronic cholestatic liver diseases.

Recent studies have demonstrated the importance of adrenergic receptors in the regulation of cholangiocarcinoma growth.18 The studies show that the cholangiocarcinoma cell lines, Mz-ChA-1 and TFK-1 express alpha2A-, alpha2B-, and alpha2C-adrenergic receptor subtypes.18 The study also shows that in Mz-ChA-1 cells, α2-adrenoreceptor stimulation (by the agonist, UK14,304) causes upregulation of cAMP, which inhibits EGF-induced MAPK activity through an acute increase of Raf-1 and sustained activation of B-Raf.18 Since alpha2-adrenergic receptor inhibition of growth occurred downstream to Ras, adrenergic stimulation or other stimulants of cAMP may overcome the Ras mutations and offer a new therapeutic approach in patients with cholangiocarcinoma.

In support of the concept that adrenergic innervation plays an important role in the regulation of cholangiocyte functions, administration of a single intraportal injection of 6-hydroxidopamine (6-OHDA, 50 mg/Kg body weight), which induces degeneration of dopaminergic terminal fibers,80,81 inhibits: (i) cholangiocyte proliferation, and the number of bile ducts; (iii) decreased secretin-stimulated choleresis and cholangiocyte cAMP levels; and (iv) increased the number of cholangiocytes undergoing apoptosis.21 Chronic administration of clenbuterol (a beta-2 adrenergic agonist)82 and dobutamine (a beta-1 adrenergic agonist)83 treatment prevents the decrease in cAMP levels and secretion induced by 6-OHDA, maintains cholangiocyte proliferation and decreasing cholangiocyte apoptosis due to 6-OHDA.21 The data suggests that degeneration/regeneration of adrenergic innervation may be important in the modulation of cholangiocyte functions in post-transplanted livers.

Furthermore, we have shown17 that cholangiocytes express the D2 (but not the D1 and D3) dopaminergic receptors and that the D2 dopaminergic agonist, quinelorane inhibits secretin-induced ductal secretion in BDL rats through activation of the Ca2+-dependent PKC gamma (but not PKC alpha, beta I and II) and inhibition of secretin-stimulated cAMP levels and PKA activity. The dopaminergic nervous system may counter-regulate secretin-stimulated ductal secretion observed in chronic liver diseases.

Summary and Future Perspectives

In this book chapter, we have summarized the recent findings related to the role of cholinergic, adrenergic and dopaminergic innervation in the regulation of cholangiocyte functions, in a fashion similar to what is shown in the gut. To date, the data summarized in this chapter indicate that the cholinergic system sustains cholangiocyte proliferation and ductal secretory activity in normal and cholestatic conditions, whereas adrenergic and dopaminergic nerves may counterbalance the stimulatory effects of the parasympathetic system on cholangiocyte proliferation and secretion. The data also suggest that nerves may also play a role in the regulation of cholangiocyte apoptosis, thus regulating ductal mass in cholangiopathies characterized by cholangiocyte proliferation/loss. These findings may have important clinical relevance for the pathophysiology of the transplanted (denervated) liver,1 where toxic,84 ischemic85 or infectious86 insults against intrahepatic bile ducts are not adequately counteracted, during the immediate post-transplant period, by efficient repair mechanisms due to the lack of nerve modulation of cholangiocyte functions.13,19-21

Further studies are necessary to evaluate the role and mechanisms of action by which the neurotransmitter serotonin may regulate cholangiocyte functions in chronic cholestasis. The rationale for these studies is based on the following known information. Serotonin is commonly synthesized and secreted by cells that display morphologic and immunohistochemical typical of endochromaffin cells. It has been shown that such cells are located in bile ducts.87 Of particular relevance is that, with cholestasis, biliary cells begin to express markers proper of endochromaffin cells.88 Our preliminary data (Marzioni and Alpini, unpublished observations, 2002) confirm such observations, and show that hyperplastic cholangiocytes overexpress chromogranin A and serotonin. The chronic administration of serotonin results in an inhibition of cholangiocyte proliferation in the BDL rat. Therefore, our data seem to suggest that neuroendocrine peptides like serotonin might be released from neighboring cells or cholangiocytes themselves in a paracrine or autocrine fashion. Bülbring et al89 originally proposed that the enterochromaffin cells in the gut are pressure-responsive sensory receptors that secrete serotonin and regulate intestinal peristalsis and secretion. Similarly, the enterochromaffin cells in the bile duct or cholangiocytes themselves may function as intraductal pressure sensors and regulate ductal secretion and the bile duct proliferative response to cholestasis. With bile duct obstruction, such as in BDL rats, upregulation of serotonin paracrine or autocrine signaling may act as an inhibitory brake to limit the cholangiocyte proliferation initiated by cholestasis. Understanding the intracellular mechanisms by which serotonin agonists regulate cholangiocyte proliferation may lead to new therapeutic approaches in patients with liver diseases. Further studies are also necessary to evaluate the factors (e.g., bile acids)77 and the transduction pathways by which nerve degeneration/regeneration occurs in chronic liver diseases. This is an important clinical problem, since reinnervation of transplanted liver is critical for the organ function, maintenance of ductal mass and for the insurgence of complications.1

Acknowledgments

Portions of the studies outlined in this chapter were supported by a grant award from Scott & White Hospital and Texas A&M University, by an NIH grant DK58411 and by VA Merit Award to Dr. Alpini.

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