| | Clinical implications of novel aspects of biliary pathophysiology☆Received 18 November 2009; accepted 11 January 2010. published online 18 February 2010. Abstract Cholangiocytes are the epithelial cells that line the biliary tree; they are the target of chronic diseases termed cholangiopathies, which represent a daily challenge for clinicians, since definitive medical treatments are not available yet. It is generally accepted that the progression of injury in the course of cholangiopathies, and promotion and progression of cholangiocarcinoma are at least in part due to the failure of the cholangiocytes’ mechanisms of adaptation to injury. Recently, several studies on the pathophysiology of the biliary epithelium have shed some light on the mechanisms that govern cholangiocyte response to injury. These studies provide novel information to help interpret some of the clinical aspects of cholangiopathies and cholangiocarcinoma; the purpose of this review is thus to describe some of these novel findings, focusing on their significance from a clinical perspective. 1. Introduction  Cholangiocytes are the epithelial cells that line the biliary tree; in normal conditions their role is to modify the bile of canalicular origin, by a wide array of absorptive and secretory processes [1], [2]. Cholangiocytes are the target of chronic diseases termed cholangiopathies [3], [4], which represent a daily challenge for clinicians, since definitive medical treatments are not available yet. As a consequence, 20% of liver transplants amongt adults and 50% among paediatric patients are caused by these disorders [5]. Cholangiopathies are heterogeneous as far as aetiology, but they share the unifying feature of being characterized by a dysregulated balance between cell growth and survival [4]. In the course of such diseases there is an impaired proliferative response to duct injury and increased cell death by apoptosis, which leads to vanishing bile ducts [3], [4] and liver failure. In addition to cholangiopathies, special attention has to be reserved for cholangiocarcinoma, a very aggressive and fatal malignancy resulting from the malignant transformation of cholangiocytes [6]. Over time, some risk factors (among which cholangiopathies are reported) for cholangiocarcinoma have been recognized [6]; however, it is common experience that the vast majority of patients affected by biliary malignancies do not show any of those conditions. Such a limited knowledge makes of cholangiocarcinoma a great challenge for clinicians, as far as surveillance, management and therapy are concerned [7]. It is generally accepted that the progression of injury in the course of cholangiopathies, and promotion and progression of cholangiocarcinoma are at least in part due to the failure of cholangiocyte mechanisms of adaptation to injury of the biliary tree. Many of those mechanisms still remain enigmatic [4], [7], [8]. In 1989, John Vierling saluted as “biliary victories” the early studies that had been published on isolated cholangiocytes [9], probably foreseeing their significance. Since then, several studies on the pathophysiology of the biliary epithelium were published, leading to highlight and understand the mechanisms driving cholangiocyte response to injury. Altogether, the findings of those studies are now providing novel information to better understand some clinical aspects of cholangiopathies and cholangiocarcinoma; the purpose of this review is thus to describe some of those findings which may be significant from a clinical perspective. 2. Biliary pathophysiology 2.1. Heterogeneity of cholangiocytes Over ten years ago, two distinct subpopulations of cholangiocytes were identified, defined as small cholangiocytes lining small ducts, and large cholangiocytes, lining large ducts [2], [10], [11], [12], [13]. Such a classification is not only based on cell size, as there are ultrastructural differences: large cholangiocytes are columnar in shape, with a wide cytoplasm filled with specialized organelles [14]. In contrast, small cholangiocytes are cuboidal, with minimal cytoplasm and inconspicuous organelles [14]. The two subpopulations differentially express a wide array of receptors, enzymes and transporters [2]. In particular, large, but not small cholangiocytes, express the receptor for secretin [10], which is considered the major activator of cholangiocyte functional activity. The interaction of secretin with its own receptors [15] leads to an increase in intracellular cAMP levels [1], [11], [12], [13], [16], activation of PKA [17], opening of CFTR Cl− channels [18] with activation of the Cl−/HCO3− exchanger (AE2) [1], [12], [17], [19], with the consequent secretion of bicarbonate into bile [20]. Similarly, only large cholangiocytes express the apical sodium-dependent bile acid transporter (ASBT or ABAT) [21]. Bile acids play a major role in governing cholangiocyte physiology and response to injury (see below), being up-taken from bile and internalized in the cytosol by ASBT. Another major difference between small and large cholangiocytes is their ability to respond to injury. One of the most commonly employed models of experimental cholestasis is bile duct ligation (BDL), to which cholangiocytes react with a marked proliferative response. Only large cholangiocytes participate to such a proliferative reaction [11]. However, small cholangiocytes are more resistant to injury: in fact, when animals are intoxicated with CCl4, large cholangiocytes undergo apoptosis, whereas small cholangiocytes proliferate, in a sort of a compensatory attempt [22]. 2.2. Role of bile acids As mentioned above, bile acids are up-taken from bile by ASBT, in a Na+ dependent fashion [21], [23], and can be dynamically excreted in the blood stream at the basolateral pole of the cell, where transporters such as MDR3 [24], a truncated form of ASBT (t-ASBT) [25] and Ost (α and β) [26] were identified. Such a polarized distribution represents the molecular basis of a vectorial recirculation of bile acids through the biliary epithelium towards hepatocytes, also known as chol-hepatic shunting. Bile acids do not pass through cholangiocytes inertly; rather, by interacting with the major intracellular signals, they affect cholangiocyte secretion, proliferation, apoptosis and differentiation [27], [28], [29], [30]. Taurocholic (TC) and taurolithocholic (TLC) acids stimulate cholangiocyte proliferation [27], whereas ursodeoxycholic acid (UDCA) inhibits cell growth in the BDL rat model [31]. However, both TC and UDCA exert anti-apoptotic effects in cholangiocytes when induced by autonomic denervation or CCl4 intoxication [32], [33], [34], [35]. Overall, bile acids are thought to be required for a proper biological response of cholangiocytes to injury: cell proliferation after BDL is markedly diminished when animals are deprived of bile acids by external drainage, yet re-gained when animals are fed with TC [36]. 2.3. Role of autonomic innervation Cholangiocytes, but not hepatocytes, express acetylcholine (ACh) receptors; ACh does not affect the functions of hepatocytes, but elicits Ca2+ increase and oscillation in isolated bile duct units (IBDUs), due to both an influx of extracellular Ca2+ and the mobilization of intracellular Ca2+ stores [37]. It has been shown that cholangiocytes express, at the basolateral domain, M3 (but not M1 and M2) ACh receptors [19]. The study also showed that ACh has no effect on the basal activity of the Cl−/HCO3− exchanger, but significantly potentiates the stimulatory effect of secretin on this exchanger [19]. Furthermore, recent data have suggested that ACh may play an even more important role as a regulator of cholangiocyte response to injury, being required for sustaining cholangiocyte proliferation and survival in cholestatic conditions. Interruption of the cholinergic innervation by vagotomy induces a marked decrease in total bile duct mass caused by both impaired cholangiocyte proliferative capacity and intracellular cAMP levels, and enhanced cell death by apoptosis [33], [38]. Rather than cholinergic innervation “per se”, it is the autonomic innervation as a whole that seems to be required to allow the adaptive reaction of cholangiocytes to cholestasis. Intact sympathetic nervous fibres are required for hepatocyte and cholangiocyte proliferation following partial hepatectomy [39]. Recent data indicate that cholangiocytes from BDL rats express alpha-1, alpha-2, beta-1 and beta-2 adrenergic receptors. If activation of alpha-1 adrenergic receptor increases secretin-stimulated ductal secretion [40], activation of alpha-2 adrenergic receptor has an inhibitory effect on ductal secretion in the course of cholestasis [41]. In a fashion similar to the cholinergic innervations, interruption of adrenergic innervations by a single intra-portal injection of 6-hydroxydopamine blunts the cholangiocyte functional and proliferative response to cholestasis and induces cell death by apoptosis [42]. Interestingly, autonomic denervation is associated to a marked reduction in ASBT expression in cholangiocytes [33]. ASBT-reduced expression is restored when rodents are fed with bile acids, along with prevention of cell death by apoptosis and loss of the proliferative response to BDL which are commonly observed, as noted above, after autonomic denervation of the liver. These findings, thus, stand as a proof of an interaction between bile acids and neurotransmitters in the regulation of cholangiocyte biology [43]. 2.4. Role of hormones and neuropeptides Estrogen play a major role in regulating cholangiocyte biology. The biliary epithelium expresses both the Estrogen receptor (ER) α and β, with their expression being up-regulated after BDL [44]. When cholangiocytes were stimulated in vitro with 17-β-estradiol, their proliferation was markedly increased. When BDL male rats were treated in vivo with anti-estrogen like tamoxifen or Ici 182,780 [45] or when BDL female rats were subjected to ovariectomy [44], cholangiocyte proliferation was markedly reduced, with induction of apoptosis [44], [45]. This evidence suggested that estrogen are required for a correct response of the biliary tree to injury. Cholangiocytes express the serotonin 1A and 1B receptors [46], the activation of which markedly reduces cholangiocyte proliferation, in association with the loss of the response to secretin, the hallmark of cholangiocyte functional activity [46]. Most interestingly, it was observed that hyperplastic cholangiocytes isolated from BDL rats are able to synthesize and secrete serotonin [46]. If, in vitro or in vivo, cholangiocyte-secreted serotonin is neutralized, cholangiocyte proliferation in response to cholestasis further increases [46]. In the course of cholestasis opioidergic neurotransmission and opioid peptide plasma and hepatic levels are markedly increased [47], [48], [49], [50], [51]. It has been also demonstrated that in the course of experimental cholestasis the mRNA for preproeenkephalin, which codes for Met- and Leu-enkephalins and Met-enkephalin containing peptides, is expressed in the liver. In addition, Met-enkephalin immunoreactivity is detected in the liver, particularly in cholangiocytes, of patients with PBC [48] and of rats with cholestasis [52]. The reason why liver cells, cholangiocytes in particular, should synthesize endogenous opioid peptides has been enigmatic for long. An answer, at least in part, to that question came from those studies that showed the expression, by cholangiocytes, of the three classic opioid receptors (δ, μ and κ OR); in the course of chronic cholestasis, the functional one is the δOR [53]. The autocrine–paracrine interaction of ligands with that receptor results in a marked inhibition of cholangiocyte proliferation, both in vivo and in vitro. When BDL rats are treated with a general opioid receptor antagonist such as naloxone, the proliferative and functional response of cholangiocytes to cholestasis is further increased [53]. Altogether, these data suggest that serotonin and endogenous opioid peptides form an autocrine loop of peptides secreted by cholangiocytes to limit their adaptive outgrowth and functional activity in reaction to cholestasis. Recent data demonstrated that a “stimulatory” autocrine/paracrine loop may exist. It has been found that cholangiocytes are the target of the growth hormone (GH)/insulin-like growth factor (IGF)-1 axis [54]: GH induces IGF-1 expression and release in isolated cholangiocytes, with the consequent stimulation of cell growth by IGF-1 [54]. Proliferating cholangiocytes from BDL rats express and secrete VEGF-A and VEGF-C [55]. By interacting with specific receptors (VEGFR-2 and VEGFR-3) they stimulate cholangiocyte proliferation, both directly and playing synergistic effects with estrogen and IGF-1 on modulation of cholangiocyte proliferation with convergence on common signalling pathways, including the ERK system [8], [55]. However, when VEGF is blocked by specific neutralizing antibodies no proliferation of peribiliary plexus (PBP) occurs in spite of BDL, suggesting that VEGF secreted by cholangiocytes drives the proliferative adaptive response of PBP to cholestasis [56]. An additional, recently discovered member of the stimulatory autocrine loop for cholangiocyte reaction to cholestasis is glucagon-like peptide-1 (GLP-1). GLP-1 is secreted by enteroendocrine L cells and modulates the biology of a number of cells, by interacting with a specific G-protein coupled receptor (GLP-1R) [57]. GLP-1 is known to modulate glucose homeostasis; specifically, it has been demonstrated that GLP-1 prevents pancreatic β-cell death by apoptosis and sustains their proliferation [57]. It was observed that GLP-1 strongly stimulates cholangiocyte growth, by interacting with a specific receptor (GLP-1R) present on cell surface [58]. Moreover, when cholangiocytes proliferate, they synthesize and release GLP-1, which subsequently acts in the microenvironment. GLP-1 becomes thus required for cell adaptive response to cholestasis: if a GLP-1R antagonist is administered to BDL rats, a marked reduction of bile duct mass and choleresis is observed [58]. In addition, GLP-1R activation is also able to prevent cholangiocyte death by apoptosis, both in vitro when induced by the exposure to toxic bile acids and in vivo in a model which combines biliary obstruction (by BDL) and cell death (CCl4 intoxication) [59]. These data gain further interest if it is considered that: (i) among its many biological properties, GLP-1 was found able to induce pancreatic ductal cells to acquire a neuroendocrine phenotype [60], [61]; (ii) pancreatic ductal cells share features in common with cholangiocytes, in terms of embryologic origin, morphology, functional activity and response to injury [62], [63]. As mentioned above, cholangiocytes themselves acquire a neuroendocrine phenotype in the course of cholestasis: what it is driven by, however, is still unclear. These recent findings indicate GLP-1 as a likely candidate. 2.5. Cytokines and inflammation Cytokines released in the course of the inflammatory process impair certain functions of the biliary epithelium. TNFα and IFNγ alter the barrier function [64], whereas pro-inflammatory cytokines alter cholangiocyte choleretic activity, by inhibiting, via the nitric oxide synthesis, adenylyl cyclase and cAMP-dependent secretion [65], [66]. Interestingly, when cholangiocytes are targeted by cytokines they respond secreting cytokines (such as IL-8, MCP-1 and CCL-28) that promote leucocyte adhesion, thus retaining cells that promote biliary cell destruction [67], [68], [69]. This can occur either directly or by amplifying the effects of bacterial products like LPS [67], [68], [69]. Similarly, it has been shown that certain auto-antibodies induce the expression, by cholangiocytes, of adhesion molecules like CD44 and Toll-like receptors, which serve as a major link between innate and adaptive immune responses and are involved in the host defence against microorganisms [70], [71]. In addition, auto-antibodies induce the secretion by cholangiocytes of a wide array of cytokines, either directly or amplifying the effect of bacterial products like LPS [71]. 3. Clinical implications Clinicians know that disorders affecting the biliary epithelium, either as chronic cholestatic diseases or as a malignancy (e.g. cholangiocarcinoma), are a challenge. Their management is hampered by the little knowledge on their pathophysiology, and, as a result of that, limited are the therapeutic options [23], [72]. Cholangiopathies are quite heterogeneous as far as aetiology, but they share two major features: (i) they progress as a result of the dysregulated balance between cell proliferation and survival; (ii) they almost selectively target either small or large bile ducts [23]. The latter feature has its paradigm in the differential target of the biliary epithelium by the two most common among the cholangiopathies, e.g. primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Such a feature has been known by clinicians for years, even if an explanation for that was missing. The above reported studies depicting the heterogeneity of the biliary epithelium, thus, gain significance once observed from a clinical point of view. The existence of these two distinct subpopulations of cholangiocytes implies that they have a differential susceptibility to injury, with different consequences in terms of alteration of their functional activity. The heterogeneity of the biliary epithelium, therefore, may account for the observation that cholangiopathies almost selectively target either small or large bile ducts [2] (Table 1). | | |  | Pathophysiological experimental evidence | Significance and clinical implications | References | |
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| Cholangiocyte heterogeneity: two different cholangiocyte subpopulations exist (e.g. small and large), which differ in morphological and biological aspects. | Cholangiopathies target either small or large bile ducts. | [1], [2], [3], [4], [5], [6], [7] | | | Cholangiocyte functional activity is regulated by secretin, which induces HCO3− in bile by the activation of the AE2 exchanger. | AE2 knockout animals develop a PBC-like phenotype. A variant of the AE2 gene discriminate patients with slower progression of PBC. | [2], [3], [4], [8], [9], [10], [11], [12], [13], [14], [15] | | | Cholangiocyte biology and response to injury is regulated by bile acids; in conditions of cholestasis and ductopenia, bile acids exert cytoprotective effects. Exacerbation of liver injury is observed in models of PSC-like cholestasis. | UDCA is the only compound to show some effects in PBC, whereas limited effects are observed in PSC. Novel perspectives are opened by nor-UDCA. | [7], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32] | | | Cholangiocytes express both adrenergic and cholinergic receptors. The autonomic innervation: (i) sustains cholangiocyte proliferation and prevent apoptosis in response to injury; (ii) maintain an adequate bile acids transporter (ASBT) in cholangiocytes. | Development of non-anastomotic biliary strictures in the transplanted (e.g. denervated) liver occurs as a consequence of impaired hepatocellular transporters. | [14], [24], [33], [34], [35], [36], [37], [38] | | | Cholangiocytes express estrogen receptors, the activation of which exert cytoprotective effects and sustain their response to injury. | PBC is more frequent in women, and its clinical breakthrough is often after menopause. Estrogen receptor expression is markedly reduced in late stage PBC. | [39], [40], [41] | | |
| | | Reactive cholangiocytes synthesize and locally release endogenous opioid peptides, which inhibit their biological response to injury. | Endogenous opioid peptides contribute to the genesis of pruritus in cholestatic patients; the administration of opiate-antagonists is effective in reducing pruritus in those patients. | [32], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53] | | | Altered response to the activation of opioid receptors is malignant cholangiocytes. | | | | |
| | | Reactive cholangiocytes synthesize and locally release serotonin, which inhibits their biological response to injury. | Administration of sertraline resulted effective in ameliorating pruritus in patients with PBC. | [32], [54], [55], [56] | | | Altered response to the activation serotonin receptors is malignant cholangiocytes. | | | | |
| | | Cholangiocyte release IGF-1 and VEGF in response to injury; they stimulate cholangiocyte biological response to injury. IGF-1 and VEGF stimulate cholangiocarcinoma cell growth. VEGF allows the expansion of the PBP. | Progression of PBC and PSC is associated with an upcoming reduction of the PBP around bile ducts. Anti-angiogenic therapies may be effective in cholangiocarcinoma. Measurement of biliary IGF-1 levels in patients with biliary strictures discriminate between cholangiocarcinoma and other causes of biliary obstruction. | [57], [58], [59], [60], [61], [62], [63], [64] | | | The activation of the GLP-1 receptor in cholangiocytes sustain proliferation and prevents apoptosis. | GLP-1 analogues are available as novel tools in the therapy of diabetes in humans. Possible effects in preventing bile duct loss in PBC patients. | [65], [66], [67], [68] | | | In response to bacterial products, auto-antibodies and cytokines, cholangiocytes express adhesion molecule and release leuco-attractant cytokines. Cytokines impair cholangiocyte functions. | In the course of cholangiopathies, cholangiocytes are exposed to bacterial products like LPS or auto-antibodies. | [69], [70], [71], [72], [73], [74], [75], [76], [77] | | | | |
The knowledge on biliary is providing more details on the mechanism that lead to the development and/or progression of cholangiopathies. Animals knocked out of the gene encoding for AE2 (the Cl−/HCO3− exchanger responsible of bicarbonate excretion in bile by cholangiocytes) develop features substantially indistinguishable from the one observed in patients affected by PBC (Table 1), such a progressive increase, over time, of the alkaline phosphatase serum levels, positivity for anti-mitochondrial auto-antibodies, inflammation of the portal space, bile duct injury progressing towards loss of bile ducts [73]. It is not surprising, therefore, that in a cohort of 258 patients affected by PBC, the presence of a variant of the AE2 gene was found associated to a mild progression of the disease, which was, in turn, aggressive in those patients in whom that variant was not found [74]. The only therapeutic approach that revealed a certain efficacy in the therapy of cholangiopathies (like PBC) is UDCA [75]. However, the mechanisms of cytoprotection and the reasons why its efficacy is limited or absent in other diseases (like PSC) are still missing. The studies on bile acid metabolism by cholangiocytes led to understand that, upon internalization, UDCA elicits anti-apoptotic signals, which make UDCA confirm its cytoprotective effects in in vivo experimental models of cholestasis and loss of bile ducts (Table 1). In contrast, when UDCA is administered to Mdr2 knockout mice, a murine model that recreates the features of PSC, it aggravates liver injury by disruption of cholangioles [76], [77]. Nor-ursodeoxycholic acid (nor-UDCA), a C [23] homologue of ursodeoxycholic acid, was recently found able to ameliorate sclerosing cholangitis in Mdr2 knockout mice [78]. Nor-UDCA actions are characterized by the following: increased hydrophilicity of bile acids; stimulated bile flow with flushing of injured bile ducts, and detoxification and elimination routes for bile acids [78]. Those properties by nor-UDCA, especially in comparison to UDCA, are not completely understood. Recently it has been proposed that the relative resistance of nor-UDCA to amidation may explain its unique physiologic and pharmacologic properties [79], which makes it a novel candidate for the therapy of cholangiopathies. The major role of bile acids in the regulation of cholangiocyte biology, may also account for other unexplained clinical observations. Given the significance of the autonomic innervations of the liver for a proper functional activity of the biliary epithelium, one would expect that it would rapidly fail after transplantation, an event that, in contrast, does not occur. An explanation for that is still missing; however it is not unlikely that bile acids may vicariate the effects of loss innervations in that condition, as the above-mentioned pathophysiologic studies suggest. As a proof of concept, the development of non-anastomotic biliary strictures after liver transplantation (e.g. in a condition of liver denervation) occurs in association with an altered bile acid metabolism, as a consequence of impaired hepatocellular transporters [80]. The recent discoveries on the role of neuroendocrine hormones and peptides in the regulation of cholangiocyte biological response to injury are shedding some light on several clinical aspects. PBC, the most common of the cholangiopathies [4], is much more frequent in women than in men, and has its clinical outcome typically after menopause, when the endogenous estrogen levels suddenly drop [4], [81]. Therefore, the observations showing estrogen as major determinant of cholangiocyte proliferation and survival provide the biological confirmation of the role of estrogen in the progression of PBC, a role that was, before, only hypothesized on the basis of epidemiological data (Table 1). To further support this concept, it has been also demonstrated that the ER expression in cholangiocytes is markedly reduced in late stages of PBC [81]. One of the peculiar symptoms of chronic cholestatic diseases is pruritus; despite that it is almost invariably present, its pathophysiology is poorly understood. Bile acids were among the hypothesized substances, being somehow “ideal”: they accumulate because of cholestasis and the employment of binding resins like cholestyramine granted certain benefits in relieving pruritus [75], [82]. However, bile acids, as much as other substances supposed to be involved, have no ability to elicit neurophysiological changes, a substantial prerequisite of peripheral pruritogens [82]. Pruritus in chronic cholestatic diseases has been associated to the action of endogenous opioid peptides. Both in the course of human and experimental cholestasis, opioid peptide plasma levels and activity are markedly increased [51], [83]. Cholestasis is associated with reduced opioid receptor expression in the central nervous system, an event that occurs as a consequence of high ligand concentration [49]. Extracts of plasma from patients with PBC-associated pruritus triggers itching in monkeys, an event that is not reproduced by plasma extracts of PBC patients without pruritus [84]. Nevertheless, the most significant evidence of increased opioidergic neurotransmission in chronic cholestasis is the wide neurological response that was often observed by clinicians when treating patients with opioid antagonists: the withdrawal-like syndrome [82], [85]. In addition to endogenous opioid peptides, pruritus of cholestasis was also shown to be at least in part due to an altered metabolism of serotonin: the administration of sertraline resulted effective in ameliorating it [75], [86] (Table 1). Endogenous opioid peptides and serotonin were then linked to chronic cholestatic under a clinical but not a pathophysiological point of view. As mentioned above, recent studies showed that both endogenous opioid peptides and serotonin are secreted by cholangiocytes in autocrine–paracrine fashion (Table 1), to limit their proliferative response to injury [46], [53]. It is thus conceivable that the genesis of the pruritus of cholestasis is elicited by the adaptive changes of cholangiocytes to injury. The clinical significance of those finding is presumably even wider: the biological effects of endogenous opioid peptides and serotonin are dysregulated in malignant cholangiocytes (stimulating, rather than inhibiting, cell proliferation), thus suggesting that the failure of those compensatory mechanisms are at the basis of cholangiocarcinoma development [87], [88]. Besides a dysregulated balance between cell proliferation and survival, progression of cholangiopathies is also thought to depend to a non-coordinated interplay between the cells involved in response to injury [8]. As mentioned above, a proper biological response of cholangiocytes relies on a parallel expansion of the PBP, which, in turn, depends on the release, by cholangiocytes of VEGF [55], [56]. Some evidences (Table 1) suggest that the progression of PSC and PBC is associated with an upcoming reduction of the number of vessels of the PBP around bile ducts [89]. Since an adequate expansion of the PBP is necessary to fulfil the metabolic needs of reactive cholangiocytes, this means that in those two diseases a condition of bile duct ischaemia is generated. Bile duct ischaemia is then responsible of the deposition of peri-ductal fibrosis [90], a hallmark of chronic cholestatic conditions. VEGF also plays a significant role in the development of cholangiocarcinoma. When cholangiocarcinoma cells are exposed to IGF-1 their proliferation is significantly increased, and VEGF and VEGF receptor expressions are induced [91], [92]. Such features imply that the growth of cholangiocarcinoma is associated with VEGF release by malignant cholangiocytes; VEGF may then both elicit a further cholangiocarcinoma growth and promote neoangiogenesis, thus playing a prominent role in the aggressiveness of such a malignancy. On this basis, experts hypothesize that the employment of VEGF receptor inhibitors (like sorafenib or bevacizumab) in patients affected by cholangiocarcinoma may be effective in relenting the development of such a malignancy [6], in a fashion similar to what it was reported for hepatocellular carcinoma (Table 1). The findings on the role of VEGF and IGF-1 in regulating cholangiocyte response to injury and cholangiocarcinoma development may also come to help to solve challenging clinical issues, such as, for example, an adequate diagnosis of nature of biliary strictures. It has been recently reported that the measurement of biliary levels of IGF-1 is able to discriminate cholangiocarcinoma from other causes of biliary strictures, either non-malignant or due to bile duct infiltration from pancreatic cancer [93] (Table 1). These data could be very useful, in perspective, especially for the surveillance of patients affected by PSC, for whom an adequate tool for early diagnosis of cholangiocarcinoma is lacking. Analogues of GLP-1, such as exendin-4 and dipeptidyil peptidase IV inhibitors, have been successfully entered in the clinical set, as novel tools for the therapy of diabetes [94]. Besides their effects on glucose homeostasis, they have long-term cytoprotective effects for pancreatic β-cells. As mentioned above, GLP-1 and exendin-4 were also found to exert similar effects also on cholangiocytes [58], [59]. Based on these data, it would be particularly attractive to test GLP-1 analogues in cholangiopathies such as PBC, in order to delay their progression by inhibiting loss of bile ducts [95] (Table 1). In the course of cholangiopathies, cholangiocytes are exposed to bacterial products like LPS or auto-antibodies [70], [96]. In line with these findings, recent data have shown that anti-cholangiocyte antibodies are expressed in the 63% of PSC and in 37% of PBC patients’ sera [70]. As mentioned, when cholangiocytes are targeted by bacterial products, auto-antibodies or cytokines, their function is altered: they express adhesion molecules and release cytokines with leuco-attractant properties. Altogether, these observations support the concept that cholangiopathies are diseases in which cholangiocytes are not only “victims”, but also active players in the disease progression. 4. The present and the future Twenty years have passed from the early “biliary victories” [9]. In this time frame the studies on biliary pathophysiology accomplished several goals, the most significant being to have clarified many aspects of cholangiocyte biology which had long been an enigma. It is necessary to mention that this field of research has progressed by keeping both pathobiological hypotheses as well as their possible clinical implications in the forefront. Such a “dual” approach allowed unveiling, as mentioned above, novel points of view that could be helpful to better understand the clinical aspects of cholangiopathies and cholangiocarcinoma. The next step is to translate the information gained into clinical practice, especially in the development of novel therapies for diseases of the biliary tree. A crucial point is the need to develop animal models that may reliably recreate human disease, and several research groups are moving ahead on this important issue [73], [76], [97], [98]. 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Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy  Corresponding author at: Department of Gastroenterology, Università Politecnica delle Marche, Nuovo Polo Didattico, III piano, Via Tronto 10, 60020 Ancona, Italy. Tel.: +39 0712206043; fax: +39 0712206044.
☆ This work was supported by a MIUR grant 2007—prot. 2007HPT7BA_002 to Dr. Marzioni and by Intramural Grants by the Università Politecnica delle Marche to Dr. Marzioni and to Dr. Benedetti. PII: S1590-8658(10)00009-5 doi:10.1016/j.dld.2010.01.005 © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Inc All rights reserved. | |
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