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Kupffer cells alter organic anion transport through multidrug resistance protein 2 in the post–cold ischemic rat liver
Author(s) -
Kudo Atsushi,
Kashiwagi Satoshi,
Kajimura Mayumi,
Yoshimura Yasunori,
Uchida Koji,
Arii Shigeki,
Suematsu Makoto
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20104
Subject(s) - multidrug resistance associated protein 2 , bone canaliculus , chemistry , excretion , organic anion transporter 1 , organic anion transporting polypeptide , endocrinology , glutathione , medicine , biochemistry , transporter , atp binding cassette transporter , enzyme , gene
Although Kupffer cells (KCs) may play a crucial role in post–cold ischemic hepatocellular injury, their role in nonnecrotic graft dysfunction remains unknown. This study examined reveal the role of KC in post–cold ischemic liver grafts. Rat livers treated with or without liposome‐encapsulated dichloromethylene diphosphonate, a KC‐depleting reagent, were stored in University of Wisconsin (UW) solution at 4°C for 8 to 24 hours and reperfused while monitoring biliary output and constituents. The ability of hepatocytes to excrete bile was assessed through laser‐confocal microfluorography in situ . Cold ischemia‐reperfused grafts decreased their bile output significantly at 8 hours without any notable cell injury. This event coincided with impaired excretion of glutathione and bilirubin‐IXα (BR‐IXα), suggesting delayed transport of these organic anions. We examined whether intracellular relocalization of multidrug resistance protein‐2 (Mrp2) occurred. Kinetic analyses for biliary excretion of carboxyfluorescein, a fluoroprobe excreted through this transporter, revealed significant delay of dye excretion from hepatocytes into bile canaliculi. The KC‐depleting treatment significantly attenuated this decline in biliary anion transport mediated through Mrp2 in the 8‐hour cold ischemic grafts via redistribution of Mrp2 from the cytoplasm to the canalicular membrane. Furthermore, thromboxane A 2 (TXA 2 ) synthase in KC appeared involved as blocking this enzyme improved 5‐carboxyfluorescein excretion while cytoplasmic internalization of Mrp2 disappeared in the KC‐depleting grafts. In conclusion, KC activation is an important determinant of nonnecrotic hepatocellular dysfunction, jeopardizing homeostasis of the detoxification capacity and organic anion metabolism of the post–cold ischemic grafts. (H EPATOLOGY 2004;39;1099–1109.)