Decreased Mrp2-Dependent Bile Flow in the Post-Warm Ischemic Rat Liver

被引:29
作者
Ban, Daisuke
Kudo, Atsushi [1 ,2 ]
Sui, Shaoguang
Tanaka, Shinji
Nakamura, Noriaki
Ito, Koji
Suematsu, Makoto [2 ]
Arii, Shigeki
机构
[1] Tokyo Med & Dent Univ, Dept Hepatobiliary Pancreat Surg, Grad Sch Med, Bunkyo Ku, Tokyo 1138519, Japan
[2] Keio Univ, Sch Med, Dept Biochem & Integrat Med Biol, Tokyo, Japan
关键词
liver; warm ischemia and reperfusion; multidrug resistance protein 2; cholestasis; microcirculatory disturbance; internalization of Mrp2; bile canalicular membrane; hepatic glutathione; biliary glutathione; MULTIDRUG-RESISTANCE PROTEIN-2; REPERFUSION INJURY; IN-VIVO; NO-REFLOW; MECHANISMS; LOCALIZATION; CHOLESTASIS; CONTRIBUTE; TRANSPORT; MEMBRANE;
D O I
10.1016/j.jss.2008.02.064
中图分类号
R61 [外科手术学];
学科分类号
摘要
Background. The link between microcirculatory disturbance and hepatocellular dysfunction remains unknown. The present study was designed to examine the key event of warm ischemia reperfusion (WIR) injury with subsequent cholestasis. Methods. A left lobar 70% ischemia and reperfusion rat model was used in this study. The portal vein and hepatic artery to the left lateral lobe of the liver were subjected to 20 min of warm ischemia followed by 60 min of reperfusion to collect bile and to measure its constituents. Results. The hepatocellular injury was increased Significantly in livers exposed to WIR, as judged by serum alanine aminotransferase. This event coincided with decreased bile production and biliary concentration of glutathione (GSH), suggesting impaired bile salts-independent bile flow, while biliary phospholipids and bile salts were not decreased. Additionally, hepatic adenosine triphosphate and GSH were not decreased after WIR. Since the biliary GSH, which is a major driving force for bile salts-independent bile flow, is excreted from hepatocytes into the bile via multidrug resistance protein 2 (Mrp2), we examined whether intracellular localization of Mrp2 occurred. Immunohistochemical analyses revealed hepatocellular Mrp2 was retrieved from bile canalicular membrane into the pericanalicular cytoplasm in the post-warm ischemic livers. Microcirculatory disturbance in livers exposed to 20 min of warm ischemia improved to levels comparable to controls. Conclusion. Mrp2 internalization, observed in this study, may play an important determinant of cholestasis in the post-warm ischemic livers. (C) 2009 Elsevier Inc. All rights reserved.
引用
收藏
页码:310 / 316
页数:7
相关论文
共 32 条
[1]   Bile secretory function after warm hepatic ischemia-reperfusion injury in the rat [J].
Accatino, L ;
Pizarro, M ;
Solís, N ;
Arrese, M ;
Koenig, CS .
LIVER TRANSPLANTATION, 2003, 9 (11) :1199-1210
[2]  
Cywes R, 1996, Liver Transpl Surg, V2, P23, DOI 10.1002/lt.500020106
[3]   Distribution of heme oxygenase isoforms in rat liver - Topographic basis for carbon monoxide-mediated microvascular relaxation [J].
Goda, N ;
Suzuki, K ;
Naito, M ;
Takeoka, S ;
Tsuchida, E ;
Tametani, T ;
Suematsu, M .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (03) :604-612
[4]  
Jaeschke H, 1998, J Hepatobiliary Pancreat Surg, V5, P402
[5]   REACTIVE OXYGEN SPECIES DURING ISCHEMIA REFLOW INJURY IN ISOLATED PERFUSED RAT-LIVER [J].
JAESCHKE, H ;
SMITH, CV ;
MITCHELL, JR .
JOURNAL OF CLINICAL INVESTIGATION, 1988, 81 (04) :1240-1246
[6]   NEUTROPHILS CONTRIBUTE TO ISCHEMIA REPERFUSION INJURY IN RAT-LIVER INVIVO [J].
JAESCHKE, H ;
FARHOOD, A ;
SMITH, CW .
FASEB JOURNAL, 1990, 4 (15) :3355-3359
[7]   Visualization of gaseous monoxide reception by soluble guanylate cyclase in the rat retina [J].
Kajimura, M ;
Shimoyama, M ;
Tsuyama, S ;
Suzuki, T ;
Kozaki, S ;
Takenaka, S ;
Tsubota, K ;
Oguchi, Y ;
Suematsu, M .
FASEB JOURNAL, 2003, 17 (01) :506-+
[8]   The canalicular multidrug resistance protein, cMRP/MRP2, a novel conjugate export pump expressed in the apical membrane of hepatocytes [J].
Keppler, D ;
Konig, J ;
Buchler, M .
ADVANCES IN ENZYME REGULATION, VOL 37, 1997, 37 :321-333
[9]   Platelet-endothelial cell interactions during hepatic ischemia-reperfusion in vivo: a systematic analysis [J].
Khandoga, A ;
Biberthaler, P ;
Messmer, K ;
Krombach, F .
MICROVASCULAR RESEARCH, 2003, 65 (02) :71-77
[10]   Conjugate export pumps of the multidrug resistance protein (MRP) family:: localization, substrate specificity, and MRP2-mediated drug resistance [J].
König, J ;
Nies, AT ;
Cui, YH ;
Leier, I ;
Keppler, D .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1999, 1461 (02) :377-394