Current Concepts in Developmental, Physiologic, and Pathophysiologic Aspects of Cholangiocyte Biology

The articles that comprise this issue of Seminars in Liver Disease address current concepts in developmental, physiologic, and pathophysiologic aspects of cholangiocyte biology. We hope that this collection will provide a timely update on this rapidly evolving field, and that it will serve as a touchstone stimulating future research in related aspects of liver function.

Normal liver function depends upon dynamic interactions between hepatocytes and other resident cell types within the liver. In 1960, original studies by Wheeler and colleagues provided convincing evidence that bile flow was not mediated exclusively by bile acid transport. Infusion into dogs of the hormone secretin stimulated a marked increase in bile flow, an increase in biliary HCO₃ ^- secretion, and alkalinization and dilution of bile.[1] Notably, secretin exerts similar regulatory effects in man, more than doubling bile flow rates without any effect on bile acid secretion.[2] Because secretin receptors are localized to cholangiocytes but not hepatocytes, this response-an increase in bile flow coupled with alkalinization and dilution of bile-emphasizes that cholangiocytes represent an essential component of the basic bile secretory unit. However, definition of the cellular mechanisms involved in cholangiocyte secretion and other processes was slow in coming due to the small size (∼8 to 20 μ), intrahepatic location, and limited number (∼2 to 5% of the nuclear mass of the liver) of cholangiocytes.

In the last decade, three major themes have provided a strong incentive to work around these technical issues and develop a clearer understanding of cholangiocyte biology. First, cholangiocytes represent an important target of injury in both developmental and acquired diseases of the liver. In pediatric patients, Alagille's syndrome and cystic fibrosis target duct development and secretory function, respectively. In older patients, autoimmune cholangitis and primary biliary cirrhosis are notable and lead to a decrease in functional duct units; and immune deficiency states, including HIV/AIDS, predispose to biliary infections. In orthotopic liver transplantation, ischemia and reperfusion injury preferentially targets cholangiocytes, and the subsequent development of rejection, duct stenosis, and vanishing bile duct syndromes all represent clinical issues of importance. Collectively, these diverse disorders all target the cholangiocyte, emphasizing the need for a more sophisticated foundation in basic biology beyond the reach of clinicians just a decade ago.

Second, cholangiocyte function is not limited to Cl^- and HCO₃ ^- secretion. Instead, cholangiocytes play diverse roles in a broad range of other liver functions as well, including paracrine signaling, immune processing, and regulation of cell growth and regeneration. For example, cholangiocytes signal to other cell types within the liver by release of ATP, a potent agonist of multiple purinergic receptors expressed by hepatocytes, stellate cells, vascular endothelium and other cholangiocytes. They appear to release endothelin and other regulatory factors as well. Moreover, there is intriguing evidence that not all cholangiocytes are created equally. Instead, there are likely to be regional differences in cholangiocyte function and capacity as small ducts coalescence into larger ducts. Certain differentiated cells are programmed for transport, while others exhibit a different capacity for proliferation and response to carcinogens.[3] The analogy to the renal tubule is attractive because there is extensive specialization of function and hormone responsiveness along the axis from proximal tubule to collecting duct.

Third, and most importantly, there is a growing appreciation for the concept that cholangiocytes represent an important target for the development of pharmacologic approaches to the treatment of liver diseases. This concept has broad potential application, including prevention of gallstones through stimulation of Cl^- and HCO₃ ^- secretion, minimizing the complications of cholestasis by stimulation of bile flow, and bypassing the secretory defect in cystic fibrosis by increasing the number and activity of alternative Cl^- channels. Success in these and other areas depends upon extending our insights into the basic mechanisms that modulate cholangiocyte growth, secretion and signaling.

The accompanying articles take advantage of the rapid progress in cholangiocyte biology that has occurred in the last several years. The application of new methods and development of new models is noteworthy. Like the fable of the blind men and the elephant, each contributing author views cholangiocytes in a different way. However, understanding the basic mechanisms that guide duct development, secretion, growth, response to injury, and carcinogenesis provide the keys to developing a new generation of pharmacologic and other tools to effectively manage the consequences of impaired cholangiocyte function. Our desire is that these articles will stimulate new studies in this area, so that the next decade will be even more exciting that the last.

REFERENCES

• 1 Wheeler H O, Ramos O L. Determinants of the flow and composition of bile in the unanesthetized dog during constant infusions of sodium taurocholate.  J Clin Invest . 1960;  39 161-170
• 2 Lenzen R, Elster J, Behrend C. Bile acid-independent bile flow is differentially regulated by glucagon and secretin in humans after orthotopic liver transplantation.  Hepatology . 1997;  26 1272-1281
• 3 Alpini G, Ulrich C, Roberts S K. Molecular and functional heterogeneity of cholangiocytes from rat liver after bile duct ligation.  Am J Physiol . 1997;  272 G289-G297