Lund M, Kang L, Tygstrup N, Wolkoff A W, Ott P
Medical Department A, National University Hospital, 2100 O Copenhagen, Denmark.
Am J Physiol. 1999 Jul;277(1):G91-100. doi: 10.1152/ajpgi.1999.277.1.G91.
Lipopolysaccharide (LPS) initiates cholestasis. Whether this process is mediated by tumor necrosis factor-alpha (TNF-alpha) and whether the cholestatic response to LPS is associated with intrahepatic accumulation of possibly toxic substances are under debate. To study these questions the hepatic uptake and biliary excretion of indocyanine green (ICG) was examined in the isolated perfused rat liver 18 h after intravenous treatment of rats with either saline, 1 mg/kg body wt LPS, or LPS and intraperitoneal pentoxifylline (POF) (n = 6 in each group). POF inhibits TNF-alpha release after LPS administration. LPS induced a typical acute-phase response with increased mRNA for acute-phase proteins, reduced albumin mRNA, and increased hepatic uptake of alanine. Intrinsic hepatic clearance of ICG in controls (1.01 +/- 0.05 ml. min(-1). g liver(-1)) was similarly decreased by LPS alone (0.62 +/- 0.04 ml. min(-1). g(-1); P = 0.002 vs. control) or combined with POF (0.66 +/- 0.06 ml. min(-1). g(-1)). A kinetic analysis indicated that LPS reduced both uptake and excretion processes in a balanced manner, so that intrahepatic ICG content was unaffected or even slightly reduced, as confirmed by measurement of ICG contents in the perfused livers. In livers from parallel-treated nonperfused rats, mRNA for the organic anion transporting protein-1 (Oatp1, which is likely to mediate ICG uptake) was unaffected by LPS, whereas the concentration of Oatp1 protein was reduced. Thus LPS induced an acute-phase response that included downregulation of ICG uptake by reduction of Oatp1 protein concentration, possibly at a posttranscriptional level. TNF-alpha appears not to be the mediator because POF did not modify these LPS effects.
脂多糖（LPS）引发胆汁淤积。该过程是否由肿瘤坏死因子-α（TNF-α）介导，以及对LPS的胆汁淤积反应是否与可能有毒物质的肝内蓄积有关，目前仍存在争议。为研究这些问题，在用生理盐水、1mg/kg体重的LPS或LPS与腹腔注射己酮可可碱（POF）静脉注射大鼠18小时后，在离体灌注大鼠肝脏中检测了吲哚菁绿（ICG）的肝摄取和胆汁排泄（每组n = 6）。POF可抑制LPS给药后TNF-α的释放。LPS诱导了典型的急性期反应，急性期蛋白的mRNA增加，白蛋白mRNA减少，肝脏对丙氨酸的摄取增加。单独使用LPS（0.62 +/- 0.04 ml·min⁻¹·g⁻¹；与对照组相比P = 0.002）或与POF联合使用（0.66 +/- 0.06 ml·min⁻¹·g⁻¹）时，对照组中ICG的内在肝清除率（1.01 +/- 0.05 ml·min⁻¹·g肝⁻¹）同样降低。动力学分析表明，LPS以平衡的方式降低了摄取和排泄过程，因此肝内ICG含量未受影响甚至略有降低，这在灌注肝脏中ICG含量的测量中得到了证实。在平行处理的未灌注大鼠的肝脏中，有机阴离子转运蛋白-1（Oatp1，可能介导ICG摄取）的mRNA不受LPS影响，而Oatp1蛋白的浓度降低。因此，LPS诱导了急性期反应，包括通过降低Oatp1蛋白浓度（可能在转录后水平）下调ICG摄取。TNF-α似乎不是介导因子，因为POF并未改变这些LPS效应。
