Chan F K, Zhang Y, Lee S S, Shaffer E A
Gastrointestinal Research Group, Department of Medicine, Faculty of Medicine, The University of Calgary, Alberta, Canada.
J Hepatol. 1998 Feb;28(2):329-36. doi: 10.1016/0168-8278(88)80021-7.
BACKGROUND/AIMS: Hepatic graft dysfunction is a major management problem in the early post-liver transplantation period. Our aims were to study how liver transplantation per se affects bile formation, and to investigate the role of cyclosporine in the pathogenesis of early graft dysfunction.
Syngeneic liver transplantation used male Lewis rats. Two weeks after transplantation, the rats were randomly assigned to receive either daily subcutaneous injections of cyclosporine 10 mg/kg for 1 week (n=8), or daily saline injections (Placebo, n=8). 24-h bile collections were performed 18 h after the last injection. Eight non-transplanted rats served as controls.
Liver transplantation per se (Placebo) significantly increased basal bile flow (51%), particularly that portion which was bile salt-independent flow (81%), but did not impair bile salt kinetics or biliary lipid composition. Cyclosporine reduced basal bile flow and bile salt-independent flow by 41% and 30%, respectively. Bile salt synthesis was 52% suppressed, leading to a 22% decrease in the bile salt pool size. The recycling frequency of the bile salt pool was unaffected. The drug inhibited bile salt (37%) and phospholipid (23%) outputs; cholesterol secretion remained unaltered. This significantly elevated the cholesterol saturation of bile (25%).
Liver transplantation per se is choleretic and does not impair bile formation or lipid composition in this inbred rat model. Parenteral administration of high-dose cyclosporine induces cholestasis by inhibiting bile salt secretion and BSIF. Bile salt synthesis is down-regulated and the bile salt pool size decreased. The drug adversely affects biliary lipid composition by differential inhibition of bile salt and phospholipid outputs relative to an unchanged cholesterol secretion.
背景/目的：肝移植术后早期，肝移植功能障碍是一个主要的管理问题。我们的目的是研究肝移植本身如何影响胆汁形成，并探讨环孢素在早期移植功能障碍发病机制中的作用。
同基因肝移植采用雄性Lewis大鼠。移植后两周，将大鼠随机分为两组，一组每天皮下注射10mg/kg环孢素，共1周（n = 8），另一组每天注射生理盐水（安慰剂，n = 8）。在最后一次注射后18小时进行24小时胆汁收集。8只未移植的大鼠作为对照。
肝移植本身（安慰剂组）显著增加基础胆汁流量（51%），特别是非胆盐依赖性胆汁流量部分（81%），但不影响胆盐动力学或胆汁脂质成分。环孢素分别使基础胆汁流量和非胆盐依赖性胆汁流量降低41%和30%。胆盐合成受到52%的抑制，导致胆盐池大小减少22%。胆盐池的循环频率未受影响。该药物抑制胆盐（37%）和磷脂（23%）的输出；胆固醇分泌保持不变。这显著提高了胆汁的胆固醇饱和度（25%）。
在这个近交系大鼠模型中，肝移植本身具有利胆作用，且不损害胆汁形成或脂质成分。大剂量环孢素胃肠外给药通过抑制胆盐分泌和非胆盐依赖性胆汁流量诱导胆汁淤积。胆盐合成下调，胆盐池大小减小。该药物通过相对于不变的胆固醇分泌对胆盐和磷脂输出的差异性抑制，对胆汁脂质成分产生不利影响。
