2. FUNCTIONAL HETEROGENEITY OF INTRAHEPATIC CHOLANGIOCYTES
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We have summarized the recent findings that demonstrate that cholangiocytes are heterogeneous with regard to morphology, secretory activity to gastrointestinal hormones/peptides and bile salts and proliferative/apoptotic responses to liver injury/toxins. On the basis of these findings, we propose a scheme for mapping the morphological, secretory, proliferative and apoptotic events in the intrahepatic biliary tree (Fig. 3). This model proposes that bile ducts are morphologically heterogeneous with small ducts lined by small cholangiocytes, and large ducts lined by large cholangiocytes. Large but not small bile ducts, express secretin and somatostatin receptors, CFTR, and Cl-/HCO3-, and respond to these two hormones with changes in ductal secretion. Pathologically, small and large ducts respond differentially to specific injury/toxins. Following BDL, only large cholangiocytes proliferate, whereas following CCl4 administration, damage and loss of large duct function leads to de novo proliferation and secretion of small cholangiocytes (resistant to CCl4) in order to compensate for the loss of large duct function. In partial hepatectomy, both small and large cholangiocytes respond with increases in proliferation and secretion. The presence of cholangiocyte heterogeneity may well endow the biliary system with physiological advantages involving bile secretion, cholehepatic shunting, and countercurrent bile and blood flow. Finally, human cholangiopathies differentially target the small and large ducts leading to cholangiocyte proliferation/loss. 2004 Elsevier Ltd. All rights reserved.