Kupffer Cells Alter Organic Anion Transport Through Multidrug Resistance Protein 2 in the Post-Cold Ischemic Rat Liver

Atsushi Rudo, Satoshi Kashiwagi, Mayumi Kajimura, Yasunori Yoshimura, Koji Uchida, Shigeki Arii, Makoto Suematsu

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


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 created 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 canaculi. 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 (TXA2) 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.

Original languageEnglish
Pages (from-to)1099-1109
Number of pages11
Issue number4
Publication statusPublished - 2004 Apr

ASJC Scopus subject areas

  • Hepatology


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