Marzioni Marco, Alpini Gianfranco, Saccomanno Stefania, de Minicis Samuele, Glaser Shannon, Francis Heather, Trozzi Luciano, Venter Juliet, Orlando Fiorenza, Fava Giammarco, Candelaresi Cinzia, Macarri Giampiero, Benedetti Antonio
Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy.
Gastroenterology. 2006 May;130(6):1831-47. doi: 10.1053/j.gastro.2006.02.021.
BACKGROUND & AIMS: There is poor knowledge on the factors that modulate the growth of cholangiocytes, the epithelial cell target of cholangiopathies, which are diseases leading to progressive loss of bile ducts and liver failure. Endogenous opioids are known to modulate cell growth. In the course of cholestasis, the opioidergic system is hyperactive, and in cholangiocytes a higher expression of opioid peptide messenger RNA has been described. This study aimed to verify if such events affect the cholangiocyte proliferative response to cholestasis.
The presence of the delta opioid receptor (OR), muOR, and kappaOR was evaluated. The effects on cholangiocyte proliferation of the in vitro and in vivo exposure to their selective agonists, together with the intracellular signals, were then studied. The effects of the OR antagonist naloxone on cell growth were also tested both in vivo and in vitro.
Cholangiocytes express all 3 receptors studied. deltaOR activation strongly diminished the proliferative and functional response of cholangiocytes to cholestasis, whereas muOR resulted in a slight increase in cell growth. The deltaOR signal is mediated by the IP3/CamKIIalpha/PKCalpha pathway, which inhibits the cAMP/PKA/ERK1/2/AKT cascade. In contrast, muOR activation stimulates the cAMP/PKA/ERK1/2/AKT cascade but does not affect the IP3/CamKIIalpha/PKCalpha pathway. The blockage of endogenous opioid peptides by naloxone further enhanced cholangiocyte growth both in vivo and in vitro.
The increase in opioid peptide synthesis in the course of cholestasis aims to limit the excessive growth of the biliary tree in the course of cholestasis by the interaction with the deltaOR expressed by cholangiocytes.
人们对调节胆管细胞生长的因素了解甚少，胆管细胞是胆管疾病的上皮细胞靶点，胆管疾病会导致胆管逐渐丧失和肝功能衰竭。已知内源性阿片类物质可调节细胞生长。在胆汁淤积过程中，阿片能系统功能亢进，并且在胆管细胞中已发现阿片肽信使核糖核酸的表达更高。本研究旨在验证这些事件是否会影响胆管细胞对胆汁淤积的增殖反应。
评估δ阿片受体（OR）、μ阿片受体和κ阿片受体的存在情况。然后研究体外和体内暴露于其选择性激动剂对胆管细胞增殖的影响以及细胞内信号。还在体内和体外测试了阿片受体拮抗剂纳洛酮对细胞生长的影响。
胆管细胞表达所有研究的3种受体。δ阿片受体激活强烈减弱胆管细胞对胆汁淤积的增殖和功能反应，而μ阿片受体则导致细胞生长略有增加。δ阿片受体信号由IP3/CamKIIα/PKCα途径介导，该途径抑制cAMP/PKA/ERK1/2/AKT级联反应。相反，μ阿片受体激活刺激cAMP/PKA/ERK1/2/AKT级联反应，但不影响IP3/CamKIIα/PKCα途径。纳洛酮阻断内源性阿片肽在体内和体外均进一步增强了胆管细胞生长。
胆汁淤积过程中阿片肽合成增加旨在通过与胆管细胞表达的δ阿片受体相互作用来限制胆汁淤积过程中胆管树的过度生长。
