Reticuloendothelial system (RES) hyperfunction and erythropoietin (Ep) production in the regenerating liver
Brian A. NaughtonDavid J. BirnbachP. LiuGail A. KolksM. Z. TungJoseph A. PilieroSam J. PilieroA. S. Gordon
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Abstract Hepatic cells in rats were evaluated after subtotal hepatectomy using scintillation scanning with technetium sulfur colloid (TSC), autoradiography, and microstereology techniques. The ability of the liver to accumulate TSC increased during the course of the regeneration as did the labeling of Kupffer and parenchymal cells with tritiated thymidine ( 3 H‐tdR). Kupffer to parenchymal cell number ratios and Kupffer cell relative areas were also elevated, attaining peak values at 72 hours post‐hepatectomy. This period corresponds to the time of peak erythropoietin (Ep) production in rats with regenerating livers after nephrectomy and exposure to hypoxia. These findings suggest that the Kupffer cell may function as a cellular site of Ep formation.Keywords:
Mononuclear phagocyte system
Kupffer cell
Parenchyma
Liver Regeneration
Thymidine
The effect of reticuloendothelial system activation on liver regeneration after 90% hepatectomy was investigated. OK-432, a killed streptococcal preparation that increases reticuloendothelial system activity, was administered to rats before 90% partial hepatectomy. Pretreated rats showed marked improvement in long-term survival: 87% (18 of 23) survived beyond 42 hr, compared with only 44.2% (24 of 52) of controls (p<0.05). Survival was determined by means of life-table analysis and regeneration response by means of bromodeoxyuridine labeling index of hepatic DNA. OK-432 pretreatment had significantly increased bromodeoxyuridine labeling index 18, 24, and 42 hr after partial hepatectomy (p<0.05). The results indicate that reticuloendothelial system activation by OK-432 before 90% partial hepatectomy enhances liver regeneration and improves survival, but these factors may not be related. The improved survival may be because of less infection in macrophage-stimulated animals or more rapid clearance of hypotension-causing vasoactive compounds. (HEPATOLOGY 1994;19:1241–1244.)
Mononuclear phagocyte system
Liver Regeneration
Bromodeoxyuridine
Immunostimulant
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The balance of phagocytic function among Kupffer cells, hepatic endothelial cells and splenic macrophages in the chronically ethanol-fed rats has been investigated. Clearance of latex particles in the blood was measured to estimate the function of the reticuloendothelial system. Phagocytosis of latex particles by Kupffer cells, hepatic endothelial cells or splenic macrophages in vivo was measured by counting the number of ingested particles in a cell after isolation of hepatic nonparenchymal cells or spleen cells following injection of different amounts of latex particles. Latex particle clearance was suppressed in the ethanol-fed rats, demonstrating a decreased phagocytic capacity of the reticuloendothelial system. Markedly decreased phagocytic function was found in 40% of Kupffer cells of the chronically ethanol-fed rats. In contrast, the number of latex particles in hepatic endothelial cells and in splenic macrophages was increased after injection of a triggering dose of latex particles. From these results it may be concluded that an increased phagocytosis of hepatic endothelial cells and splenic macrophages could compensate for the decreased phagocytic function of Kupffer cells.
Mononuclear phagocyte system
Kupffer cell
Liver cytology
Phagocytic Cell
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To ascertain the effects of selective impairment of the fixed macrophage compartment on host defense, rabbit anti-rat Kupffer cell serum was raised and tested for its ability to depress phagocytosis and to serve as an immunosuppressant. The ability of the anti-Kupffer cell serum (AKS) to depress intravascular clearance rates of gelatinized RE test lipid emulsion indicated that the antiserum can functionally impair overt phagocytic activity. The phagocytic impairment was manifested by a significantly decreased liver phagocytosis of the lipid emulsion, whereas only a slight decrease in phagocytosis by the spleen was noted. When titered in vitro, AKS was cytotoxic to hepatic and splenic macrophages. Although AKS induced some degree of immunosuppressive activity, it was not as effective as antilymphocytic serum in suppressing the humoral immune response of rats to sheep red blood cells. Selectivity in the cytotoxic activity of AKS was manifested by toxicity for macrophages but not toxicity for thymocytes or splenic lymphocytes. It is suggested that AKS as a specific antimacrophage serum may be useful for assessing the contribution of the reticuloendothelial system to host defense physiology and metabolism.
Mononuclear phagocyte system
Kupffer cell
Humoral immunity
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Although previous work suggests that tumor necrosis factor-alpha (TNF) promotes liver regeneration after partial hepatectomy (PH), the source of TNF is unknown. If Kupffer cells release TNF after PH, then Kupffer cell depletion by gadolinium chloride (GdCl) should inhibit liver regeneration. To test this hypothesis, cytokine expression and regenerative events were compared in GdCl-treated and control rats. Functional assays and Northern blot analysis of a Kupffer cell-specific mRNA confirmed that GdCl depleted Kupffer cells. Despite this, semiquantitative reverse transcription-polymerase chain reaction analysis of total hepatic RNA showed six- to eightfold higher levels of TNF transcripts in GdCl-treated rats. In this group, PH caused 12-to 16-fold greater induction of interleukin-6, a TNF-inducible cytokine, and two- to threefold greater induction of several cytokine-regulated genes (c-jun, C/EBP-beta, and C/EBP-delta). GdCl also amplified regeneration-associated increases in the DNA binding activity of AP-1, a growth regulatory transcription factor. Furthermore, hepatic incorporation of [3H]thymidine, expression of the S-phase antigen, proliferating cell nuclear antigen, and the hepatocyte mitotic index were each significantly greater in GdCl-treated rats. Thus, although GdCl causes Kupffer cell depletion, it does not decrease liver TNF and actually enhances liver regeneration after PH.
Liver Regeneration
Kupffer cell
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Liver Regeneration
Kupffer cell
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Liver Regeneration
Kupffer cell
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Kupffer cell
Mononuclear phagocyte system
Phagocytic Cell
Hepatotoxin
Phagocyte
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The effect of reticuloendothelial system activation on liver regeneration after 90% hepatectomy was investigated. OK-432, a killed streptococcal preparation that increases reticuloendothelial system activity, was administered to rats before 90% partial hepatectomy. Pretreated rats showed marked improvement in long-term survival: 87% (18 of 23) survived beyond 42 hr, compared with only 44.2% (24 of 52) of controls (p < 0.05). Survival was determined by means of life-table analysis and regeneration response by means of bromodeoxyuridine labeling index of hepatic DNA. OK-432 pretreatment had significantly increased bromodeoxyuridine labeling index 18, 24, and 42 hr after partial hepatectomy (p < 0.05). The results indicate that reticuloendothelial system activation by OK-432 before 90% partial hepatectomy enhances liver regeneration and improves survival, but these factors may not be related. The improved survival may be because of less infection in macrophage-stimulated animals or more rapid clearance of hypotension-causing vasoactive compounds.
Mononuclear phagocyte system
Liver Regeneration
Bromodeoxyuridine
Immunostimulant
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The liver has a remarkable proliferative capacity after a partial hepatectomy. Previous studies have indicated that Kupffer cells have the potential to exert both stimulatory and inhibitory influences on hepatocyte proliferation. To elucidate the role of Kupffer cells in liver regeneration, mice were selectively depleted of Kupffer cells by injection of liposome-encapsulated dichloromethylene diphosphonate (lipo-MDP) at day 3 after a two-thirds hepatectomy. Results showed that liver regeneration was delayed after Kupffer cell-depletion. In control mice, hepatocyte growth factor (HGF) mRNA expressions were enhanced during liver regeneration and expressions of HGF were localized in fat-storing cells (Ito cells). In Kupffer cell-depleted mice, the number of HGF-expressing cells decreased in the regenerating liver, and expressions of HGF and its receptor (c-met) as well as other growth factors/cytokines were less prominent than in control mice. In contrast, expressions of TNF-α, another potent cytokine involved in liver regeneration, did not differ between Kupffer cell-depleted and control mice during the regeneration. Administration of TNF-α antibody did not reduce the expression of HGF or liver regeneration. These findings imply that Kupffer cells play a stimulatory role in liver regeneration by enhancing HGF expression via TNF-α-non-mediated mechanisms.
Liver Regeneration
Kupffer cell
Liver cytology
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The cellular basis of Kupffer-cell phagocytosis blockade induced by gadolinium chloride was studied in rats. Investigations with heterologous erythrocytes labelled with 51Cr show that the gadolinium chloride-induced reticuloendothelial blockade is due to the depressed phagocytic activity of the Kupffer cells. Our light-microscopic studies indicate that, as a result of the action of gadolinium chloride, the impaired Kupffer-cell phagocytosis is observed not only in normal, non-activated Kupffer cells, but also in those activated with a reticuloendothelial stimulant, Zymosan. Our electron-microscopic investigations suggest that the failure of the Kupffer cells to incorporate carbon during the reticuloendothelial blockage induced by this rare earth metal chloride is due to defects in the surface attachment and in the engulfment phases of phagocytosis.
Mononuclear phagocyte system
Kupffer cell
Zymosan
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