Participation of Hepatic Macrophages and Plasma Factors in Endotoxin-Induced Liver Injury

Fujita, Shin-ichi; Arii, Shigeki; Monden, Kazunobu; Adachi, Yoshifumi; Funaki, Naomi; Higashitsuji, Hiroaki; Furutani, Masaharu; Mise, Masahiro; Ishiguro, Shigeo; Kitao, Tadahiro; Nakamura, Toshio; Imamura, Masayuki

doi:10.1006/jsre.1995.1163

Cited by 30 publications

(29 citation statements)

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“…However, because GdCl destroys all Kupffer cells (Hardonk et al, 1992), these data indicate that other factors, not Kupffer cells alone, mediate the effects of LPS on the regulation of hepatic transporters. This possibility is supported by an earlier study showing that both the activation of Kupffer cells, as well as some undetermined circulating plasma factors in animals where Kupffer cells had been destroyed, were capable of causing the occurrence and development of LPS-induced liver injury (Fujita et al, 1995).…”

Section: Lps-mediated Regulation Of Hepatic Transportersmentioning

confidence: 65%

LIPOPOLYSACCHARIDE-MEDIATED REGULATION OF HEPATIC TRANSPORTER mRNA LEVELS IN RATS

Cherrington¹,

Slitt²,

Li³

et al. 2004

Drug Metab Dispos

137

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ABSTRACT:The function of hepatic transporters is to move organic substances across sinusoidal and canalicular membranes. During extrahepatic cholestasis, transporters involved in the movement of substances from blood to bile, such as sodium/taurocholate-cotransporting polypeptide (Ntcp) and multidrug resistance protein 2 (Mrp2), are down-regulated, whereas others that transport chemicals from liver to blood, such as Mrp3, are up-regulated. Unlike extrahepatic cholestasis, where transporter expression responds to the stress of accumulating bile constituents, lipopolysaccharide (LPS)-induced intrahepatic cholestasis may be directly caused by alterations in transporter expression. The aim of this study was to quantitatively determine the effect of LPS on transporter expression and study the mechanism(s) by which LPS alters mRNA levels of major hepatic transporters in Sprague-Dawley rats. Hepatic mRNA levels of Mrp2, Mrp6, multiple drug resistance protein 1a (Mdr1a), organic anion-transporting polypeptide 1 (Oatp1), Oatp2, Oatp4, Ntcp, bile salt export pump, organic cation transporter 1 (Oct1), and organic anion transporter 3 (Oat3) were dramatically decreased, beginning approximately 6 h after LPS administration, whereas Mrp5 and Oat2 levels were unchanged. In contrast, LPS increased mRNA levels of Mrp1, Mrp3, and Mdr1b concurrently with the down-regulated transporters. Pretreatment with dexamethasone, which decreases the release of cytokines, reversed the reduction of Mdr1a, Oatp1, Oatp2, Oct1, and Ntcp mRNA following LPS administration. Furthermore, dexamethasone pretreatment also prevented the LPS-mediated increase in Mrp1, Mrp3, and Mdr1b, whereas pretreatment with aminoguanidine or gadolinium chloride, an inhibitor of inducible nitric oxide synthetase and a Kupffer cell toxicant, respectively, had no effect on the LPSinduced changes. The concurrent repression and induction of various transporters, as well as dexamethasone abatement of both LPS-mediated repression and induction, indicates that these responses may be mediated through similar pathways.

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Section: Lps-mediated Regulation Of Hepatic Transportersmentioning

confidence: 65%

LIPOPOLYSACCHARIDE-MEDIATED REGULATION OF HEPATIC TRANSPORTER mRNA LEVELS IN RATS

Cherrington¹,

Slitt²,

Li³

et al. 2004

Drug Metab Dispos

137

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“…The effects of GdCl 3 on Kupffer cells are reported to be manifold in nature and more complex than merely a possible change in cell number, including: the induction of apoptosis; 24 the reduction of nitric oxide synthase expression, 25 the decrease of phagocytic activity, 26 probably by interfering with calciumdependent cell surface interactions; 27,28 and attenuation of endotoxin-induced TNF-α mRNA production and protein release; 26,29,30 and impairment of their capacity to generate superoxide; 31 the abolition of expression of certain cell-specific antigens; 32 and the switch of phenotypic shape with loss of IL-10 expression. 33 Both TNF-α and IL-10 have been related to inflammation, necrosis and fibrosis of the liver; 34 thus inhibition of their expression in Kupffer cells by GdCl 3 , 26,29,30,34 may explain the beneficial effects observed in this study, mainly in the prevention of fibrosis, and the partial prevention of necrosis, evidenced by ALT serum levels and by histopathological analysis. Moreover, the reported capability of GdCl 3 to impair the Kupffer cells' ability to generate superoxide 31 is in concordance with the prevention of the increase in lipid peroxidation observed herein, which in turn is associated with necrosis, cholestasis and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride

Muriel

Escobar

2003

J of Applied Toxicology

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Inhibition of Kupffer cells could disrupt the sequence of events leading to organ injury by damping down the fibrogenic stimulus. To elucidate the role of Kupffer cells in liver fibrosis and cirrhosis, rats were treated with gadolinium chloride (GdCl(3)) and cirrhosis was induced by subchronic carbon tetrachoride (CCl(4)) administration. Carbon tetrachloride was administered three times per week for 8 weeks to male Wistar rats treated simultaneously with GdCl(3) (20 mg kg(-1), i.p. daily); appropriate controls were performed. Serum enzyme activities of alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (gamma-GTP) and alanine aminotransferase (ALT) and bilirubin concentration increased significantly by CCl(4), whereas GdCl(3) prevented completely the increase in gamma-GTP and partially prevented the increase in ALP, ALT and bilirubins (P < 0.05). Liver glycogen was depleted by CCl(4), an effect that GdCl(3) was not capable of preventing. Moreover, gadolinium by itself depleted it. Lipid peroxidation increased about 2.5-fold by administration with CCl(4), whereas GdCl(3) preserved lipid peroxidation within normal values. Hepatic collagen increased threefold after subchronic intoxication with CCl(4) (P < 0.05) whereas GdCl(3) prevented partially (P < 0.05) the increase in collagen content, as evidenced by the liver hydroxyproline content and by the histopathological analysis. The present results suggest that Kupffer cells are needed for the production of CCl(4)-induced cirrhosis, because their inactivation with GdCl(3) prevents the disease.

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“…GdCl 3 causes a 70% reduction in the phagocytosis of radiolabeled bacteria (11). GdCl 3 most likely is protective because it reportedly prevents the release of inflammatory cytokines and toxic oxygen radicals such as superoxide anion produced by activated Kupffer cells (7,(12)(13)(14)(15)(16)(17)(18)(19). However, we have not yet encountered the phenomenon in which GdCl 3 improves the survival of endotoxemia in normal mice.…”

Section: Introductionmentioning

confidence: 85%

Opposite Effects of Enhanced Tumor Necrosis Factor-?? Production From Kupffer Cells by Gadolinium Chloride on Liver Injury/Mortality in Endotoxemia of Normal and Partially Hepatectomized Mice

Kinoshita¹,

Uchida²,

Nakashima³

et al. 2005

Shock

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Gadolinium chloride (GdCl3) reportedly inhibits Kupffer cell function including TNF-alpha production and thereby improves organ dysfunctions after LPS challenge, particularly in partially hepatectomized (PH) mice. In addition, TNF-alpha reportedly promotes the regeneration of hepatocytes after PH. However, we have frequently seen GdCl3 treatment increase the mortality of normal mice after LPS injection. Therefore, we investigated this controversial issue in the present study. The mice treated by GdCl3 (10 mg/kg, i.v.) at 24 h before LPS challenge showed increased serum TNF-alpha and ALT levels after LPS challenge and a decreased mouse survival rate. The Kupffer cells from GdCl3-treated mice consistently produced a much larger amount of TNF-alpha following in vitro LPS stimulation than those of the control mice despite the fact that the Kupffer cells decreased in number and also demonstrated decreased superoxide production. Anti-TNF-alpha Ab before LPS-injection greatly improved GdCl3-induced mouse mortality and the degree of liver injury. In marked contrast, the increased amount of TNF-alpha induced by GdCl3 improved the survival after LPS challenge in PH mice because TNF-alpha promoted hepatocyte mitosis/regeneration in PH liver as evidenced by the fact that the inhibition of TNF-alpha before PH suppressed hepatocyte regeneration and decreased survival after LPS challenge. In conclusion, GdCl3 depletes the superoxide-producing Kupffer cells but conversely enhances the function of TNF-alpha-producing Kupffer cells, which thereby leads to LPS-induced mortality. Meanwhile, the increased TNF-alpha production induced by GdCl3 supports liver regeneration and increases the survival after LPS challenge in PH mice.

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Participation of Hepatic Macrophages and Plasma Factors in Endotoxin-Induced Liver Injury

Cited by 30 publications

References 0 publications

LIPOPOLYSACCHARIDE-MEDIATED REGULATION OF HEPATIC TRANSPORTER mRNA LEVELS IN RATS

LIPOPOLYSACCHARIDE-MEDIATED REGULATION OF HEPATIC TRANSPORTER mRNA LEVELS IN RATS

Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride

Opposite Effects of Enhanced Tumor Necrosis Factor-?? Production From Kupffer Cells by Gadolinium Chloride on Liver Injury/Mortality in Endotoxemia of Normal and Partially Hepatectomized Mice

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