Kubitz R, Wettstein M, Warskulat U, Häussinger D
Medizinische Universitätsklinik, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany.
Gastroenterology. 1999 Feb;116(2):401-10. doi: 10.1016/s0016-5085(99)70138-1.
BACKGROUND & AIMS: Endotoxin lipopolysaccharide (LPS) induces cholestasis and down-regulates the multidrug resistance protein 2 (MRP2). This study intends to characterize the short-term effects of LPS on MRP2.
The effects of LPS and dexamethasone on excretion of bromosulphalein (BSP), MRP2 messenger RNA (mRNA) levels, and subcellular MRP2 localization were studied by means of liver perfusion, Northern blots, and confocal microscopy.
LPS treatment for 3-12 hours decreased biliary BSP excretion (10 micromol/L) by 40%. Hyposmolarity stimulated BSP excretion to control levels 3 hours after LPS injection, but was ineffective after 12 hours or in saline-treated controls. LPS led to a strong decrease of MRP2 mRNA after 12 hours, but not during the first 6 hours. LPS induced the appearance of MRP2 in intracellular vesicles in the immediate vicinity of the canaliculi within 3 hours, and these vesicles were remote from the canaliculi after 6 and 12 hours. The MRP2-containing vesicles did not stain for dipeptidylpeptidase IV (DPPIV). Dexamethasone counteracted the LPS effects on MRP2 mRNA levels, subcellular distribution, and BSP excretion.
LPS induces cholestasis due to an early retrieval of MRP2 from the canalicular membrane, whereas down-regulation of MRP2 mRNA is a later event. LPS-induced MRP2 retrieval from the canalicular membrane is not associated with the retrieval of DPPIV, suggestive for selectivity of the process.
内毒素脂多糖（LPS）可诱导胆汁淤积并下调多药耐药蛋白2（MRP2）。本研究旨在描述LPS对MRP2的短期影响。
通过肝脏灌注、Northern印迹法和共聚焦显微镜研究LPS和地塞米松对溴磺酞（BSP）排泄、MRP2信使核糖核酸（mRNA）水平及MRP2亚细胞定位的影响。
LPS处理3 - 12小时可使胆汁中BSP排泄（10微摩尔/升）降低40%。低渗刺激LPS注射3小时后BSP排泄恢复至对照水平，但12小时后无效，且在生理盐水处理的对照组中也无效。LPS在12小时后导致MRP2 mRNA显著下降，但在最初6小时内未出现这种情况。LPS在3小时内诱导MRP2出现在紧邻胆小管的细胞内小泡中，而在6小时和12小时后这些小泡远离胆小管。含MRP2的小泡未被二肽基肽酶IV（DPPIV）染色。地塞米松可抵消LPS对MRP2 mRNA水平、亚细胞分布和BSP排泄的影响。
LPS诱导胆汁淤积是由于早期MRP2从胆小管膜上被回收，而MRP2 mRNA的下调是后期事件。LPS诱导的MRP2从胆小管膜上的回收与DPPIV的回收无关，提示该过程具有选择性。
