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 journalArticle

31 Citations (Scopus)

Abstract

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
JournalHepatology
Volume39
Issue number4
DOIs
Publication statusPublished - 2004 Apr

Fingerprint

Kupffer Cells
Anions
Transplants
Liver
Bile
Hepatocytes
Thromboxane-A Synthase
Cold Ischemia
Wounds and Injuries
P-glycoprotein 2
Bilirubin
Glutathione
Cytoplasm
Lasers
Homeostasis
Coloring Agents
Membranes
Enzymes

ASJC Scopus subject areas

  • Hepatology

Cite this

Kupffer Cells Alter Organic Anion Transport Through Multidrug Resistance Protein 2 in the Post-Cold Ischemic Rat Liver. / Rudo, Atsushi; Kashiwagi, Satoshi; Kajimura, Mayumi; Yoshimura, Yasunori; Uchida, Koji; Arii, Shigeki; Suematsu, Makoto.

In: Hepatology, Vol. 39, No. 4, 04.2004, p. 1099-1109.

Research output: Contribution to journalArticle

Rudo, Atsushi ; Kashiwagi, Satoshi ; Kajimura, Mayumi ; Yoshimura, Yasunori ; Uchida, Koji ; Arii, Shigeki ; Suematsu, Makoto. / Kupffer Cells Alter Organic Anion Transport Through Multidrug Resistance Protein 2 in the Post-Cold Ischemic Rat Liver. In: Hepatology. 2004 ; Vol. 39, No. 4. pp. 1099-1109.
@article{3a60d0a46717458ab19e6f32c1873f74,
title = "Kupffer Cells Alter Organic Anion Transport Through Multidrug Resistance Protein 2 in the Post-Cold Ischemic Rat Liver",
abstract = "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.",
author = "Atsushi Rudo and Satoshi Kashiwagi and Mayumi Kajimura and Yasunori Yoshimura and Koji Uchida and Shigeki Arii and Makoto Suematsu",
year = "2004",
month = "4",
doi = "10.1002/hep.20104",
language = "English",
volume = "39",
pages = "1099--1109",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "4",

}

TY - JOUR

T1 - Kupffer Cells Alter Organic Anion Transport Through Multidrug Resistance Protein 2 in the Post-Cold Ischemic Rat Liver

AU - Rudo, Atsushi

AU - Kashiwagi, Satoshi

AU - Kajimura, Mayumi

AU - Yoshimura, Yasunori

AU - Uchida, Koji

AU - Arii, Shigeki

AU - Suematsu, Makoto

PY - 2004/4

Y1 - 2004/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=1842584562&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1842584562&partnerID=8YFLogxK

U2 - 10.1002/hep.20104

DO - 10.1002/hep.20104

M3 - Article

VL - 39

SP - 1099

EP - 1109

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 4

ER -