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At least 19 recordsLinked to original sources
PubMed1975

Electron microscopy of Kupffer cells in the orthotopic porcine liver homograft during the late stage after transplantation (phagocytosis of host cells by Kupffer cells).

Electron microscopical observations of macrophages (Kupffer cells) in the orthotopic porcine liver homograft in later stages after transplantation are described and demonstrated. The findings show close topographical relations between the Kupffer cells and hepatocyte debris, erythrocytes, thrombocytes, lymphocytes and granulocytes. Besides an uptake of hepatocyte debris, a phagocytosis and degradation of apparently unaltered erythrocytes, thrombocytes and probably also lymphocytes by the macrophages were observed. The possible significance of these findings is discussed with regard to the immunological interactions between macrophages and lymphocytes, to the course of the rejection in the liver homograft, to the effect on the blood cells and platelets of the host organism, and thus to the long-term prognosis of liver transplantation.

Animals↗
PubMed1989

Comparative study of cytotoxicity, tumor necrosis factor, and prostaglandin release after stimulation of rat Kupffer cells, murine Kupffer cells, and murine inflammatory liver macrophages.

Macrophages (Mphi) and Mphi-depleted (nonadherent) nonparenchymal cells (NPC) of the liver were examined for their cytotoxic potential against tumor cells, production of tumor necrosis factor (TNF), and release of prostaglandins (PG) following stimulation by lipopolysaccharide (LPS), interferon-gamma (IFN gamma), and zymosan. Resident murine liver macrophages had no natural cytotoxicity for the TNF-resistant target cell line P815. Activation of these cells was only obtained by a combination of IFN gamma and LPS. Inflammatory murine macrophages were in a primed stage and could be activated by LPS alone in the absence of IFN gamma. Rat resident macrophages resembled functionally the inflammatory macrophages of the mouse liver rather than the resident macrophages. They displayed natural cytotoxicity against all targets tested and were further activated by LPS in the absence of IFN gamma. Similar results were obtained with respect to macrophage-depleted nonadherent NPC: Mouse NPC had a low level of NK activity against Yac-1 cells. Treatment with pyran copolymer resulted in a strong increase of cytotoxicity against Yac-1; furthermore, a TNF-dependent killing of Wehi 164 and TNF-independent cytotoxicity against P815 cells were now acquired. In the rat NPC prepared from unstimulated animals expressed high levels of natural cytotoxicity against all targets. No major differences could be observed between inflammatory Mphi and Kupffer cells of rat and mouse liver with regard to TNF production and TNF-dependent killing of Wehi 164 tumor cells. The same was true for the spectrum of secreted prostanoids. Upon activation of all cell populations a marked shift toward the production of PGE2 occurred. Experiments involving the cyclooxygenase inhibitor indomethacin showed enhanced TNF-dependent tumor cell killing by nonactivated Mphi in the absence of prostanoid production.

Animals↗
PubMed1991

Identification and induction of cytochrome P450 2E1 in rat Kupffer cells.

Kupffer cells, the resident macrophages of the liver, have a well characterized role in the removal of blood-born foreign substances by phagocytosis. Because Kupffer cells may contribute to hepatic xenobiotic metabolism, the current studies evaluated the presence and inducibility of P450 2E1 in rat Kupffer cells. Hepatocytes and Kupffer cells were isolated from the livers of control and acetone-treated (1% v/v acetone in the drinking water for 7 days) rats. P450 2E1 was immunochemically detectable at low levels in Kupffer cell homogenates from untreated rats and was induced greater than 10-fold by acetone-treatment. The presence of P450 2E1 in Kupffer cells from untreated rats was confirmed by inhibition of benzene hydroxylation with anti-P450 2E1 immunoglobulin G. Benzene hydroxylase activity was induced 16.3-fold in Kupffer cells isolated from acetone-treated rats and remained 70% inhibitable by anti-P450 2E1 antibody. The benzene hydroxylase activity of hepatocytes from the same animals was induced 3.9-fold by acetone treatment. The specific activity for benzene hydroxylation of Kupffer cell homogenates from acetone-treated rats was nearly equal to that for the hepatocytes from the same animals. The presence and inducibility of P450 2E1 in Kupffer cells suggests that, under conditions where P450 2E1 is induced, Kupffer cell-generated metabolites may contribute to Kupffer cell toxicity, as well as general hepatic injury.

Acetone↗
PubMed1990

Fine structure and function of Kupffer cells.

Kupffer cells are macrophages that are attached to the luminal surface or inserted in the endothelial lining of hepatic sinusoids. In this site, Kupffer cells play a key role in host defense by removing foreign, toxic and infective substances from the portal blood and by releasing beneficial mediators. Under some conditions, toxic and vasoactive substances also are released from Kupffer cells which are thought to play a role in a variety of liver diseases. Many of these activities may be modulated by the levels of gut derived endotoxin normally present in the portal blood. The ultrastructural aspects of Kupffer cell structure function in situ are best studied using perfused-fixed livers. In fixed livers, transmission and scanning electron microscopy reveal Kupffer cells during health to be irregular in shape with their exposed surfaces presenting numerous microvilli, filopodia, and lamellopodia. Long filopodia penetrate endothelial fenestrae to secure Kupffer cells to the sinusoid lining. Specific membrane invaginations known as worm-like bodies or vermiform processes are seen in the cytoplasm of Kupffer cells as are numerous endocytotic vesicles and lysosomes which vary in density, shape and size. Sometimes, annulate lamellae connected to the rough endoplasmic reticulum also are found. The principal endocytic mechanisms of Kupffer cells are phagocytosis of particulates and cells, and bristle-coated micropinocytosis for fluid-phase endocytosis of smaller substances. Many of these events are mediated by specific receptors. In some species, Kupffer cells can be distinguished from other sinusoidal lining cells and monocytes by specific cytoplasmic staining or monoclonal antibodies. Kupffer cells have been shown to be of monocytic origin as well as having the capacity for self-replication.

Humans↗
PubMed1990

Interdependence of tumor necrosis factor, prostaglandin E2, and protein synthesis in lipopolysaccharide-exposed rat Kupffer cells.

Kupffer cells are the main producers of tumor necrosis factor-alpha (TNF; cachectin) and eicosanoids in the liver exposed to lipopolysaccharide (endotoxin; LPS). A very rapid but transient release of TNF is followed by a slow, steady synthesis of prostaglandin E2 (PGE2). TNF itself is able to provoke eicosanoid synthesis in Kupffer cells; the rate and pattern of prostaglandin production are similar to those observed after treatment with LPS. Anti-TNF antibodies completely neutralize TNF action on Kupffer cells, thus ruling out any participation of contaminating LPS. LPS stimulation of PGE2 production in Kupffer cells is reduced by the antiserum to 50%, indicating an involvement of TNF in the stimulatory action of LPS. On the other hand, PGE2, a potent inhibitor of LPS-elicited TNF release, is able to suppress LPS- but not TNF-stimulated eicosanoid synthesis in rat Kupffer cells. In addition to this autocrine circuit, extrahepatic factors participate in the regulation of Kupffer cell activation: glucocorticoids not only inhibit TNF or prostaglandin production, they also reverse the LPS-specific changes in the prostaglandin pattern of Kupffer cells. LPS, TNF or cycloheximide when given alone in the concentration range applied in this study do not affect the viability of rat Kupffer cells. However, the combinations of cycloheximide and either LPS or TNF cause rapid death of the cultured cells. The cytolytic potential of either combination cannot be alleviated by treatment with glucocorticoids.

Animals↗
PubMed1988

Release of peptide leukotrienes from rat Kupffer cells.

Kupffer cells isolated from the normal rat liver were incubated with calcium ionophore A23187, and the levels of peptide leukotrienes (LTC4, LTD4, and LTE4) contained in the culture supernatant were determined by the combined technique of reverse-phase high-performance liquid chromatography and radioimmunoassay. In response to A23187, Kupffer cells released LTC4, LTD4, and LTE4. After 10 min-preincubation of Kupffer cells with AA861, a 5-lipoxygenase inhibitor, the generation of LTC4, LTD4, and LTE4 from A23187-stimulated Kupffer cells was significantly suppressed. Platelet activating factor (PAF), a phospholipid mediator, significantly enhanced the release of LTC4, LTD4, and LTE4 from Kupffer cells stimulated with A23187. These results suggested that Kupffer cells may participate in inflammatory and immunologic events in the liver tissue by the release of peptide leukotrienes.

Animals↗
PubMed1988

Beta-glucuronidase and chloroacetate-esterase staining discriminates rat liver sinusoidal endothelial cells from Kupffer cells in primary culture.

Beta-glucuronidase and N-AS-D-chloroacetate esterase cytochemistry have been applied to rat liver sinusoidal endothelial cells and Kupffer cells. Both staining procedures allowed a clear-cut differentiation of either cell type. Kupffer cells which had been stained with beta-glucuronidase showed a positive reaction, whereas sinusoidal endothelial cells were completely negative. If the chloroacetate reaction was used, the former stained diffusely while the latter showed a characteristic granular staining pattern. Identity and purity of sinusoidal endothelial cells and Kupffer cells was validated by transmission and scanning electron microscopy as well as by the pattern of released eicosanoids which is characteristic for either cell type. These two staining techniques are a valuable addition to the peroxidase reaction commonly applied for differentiation.

Animals↗
PubMed1989

Comparison of sulphated glycosaminoglycan and hyaluronate synthesis and secretion in cultured hepatocytes, fat storing cells, and Kupffer cells.

The extracellular matrix of normal liver contains several types of proteoglycans including heparan sulphate, chondroitin sulphate isomers, dermatan sulphate, and the glycosaminoglycan, hyaluronic acid. In the present study both the synthesis and secretion as well as the pattern of radioactively labeled proteoglycans and hyaluronic acid of hepatocytes, fat-storing cells (Ito cells), and Kupffer cells maintained in monolayer cultures under mostly identical conditions were compared to assess their relative contribution to hepatic proteoglycan synthesis. Fat-storing cells were identified as the main type of cell producing and secreting proteoglycan and hyaluronic acid. More than 70% of labeled proteoglycan and hyaluronic acid were secreted into the medium. Heparan sulphate is the main type of proteoglycan in hepatocytes, whereas in the medium of fat-storing cells, chondroitin sulphate and dermatan sulphate comprise the major fractions. Hyaluronic acid was not detectable in hepatocyte cultures and found only in low amounts in the medium of Kupffer cells. The results point to a stringent quantitative and qualitative cellular compartmentation of proteoglycan synthesis in liver with fat-storing cells as the most important cell type for matrix proteoglycan and hyaluronic acid production.

Adipose Tissue↗
PubMed1990

Electron microscopic observations on the accumulation of large granular lymphocytes (pit cells) and Kupffer cells in the liver of rats treated with continuous infusion of interleukin-2.

Treatment schedules were investigated for in vivo induction of lymphokine-activated killer cells in the rat liver. Treatment of rats with continuous systemic or regional infusion of recombinant human interleukin-2 with a dose of 4 to 8 x 10(4) U/day during 7 days, resulted in an increase in number of large granular lymphocytes or pit cells in the liver up to 43 times normal. Kupffer cells, nongranular lymphocytes, monocytes and neutrophils also increased in number, but with a maximal fivefold increase this was much less pronounced than for large granular lymphocytes. Kupffer cells showed morphological signs of activation and were frequently seen in mitosis. Frequent mitoses were also observed for large granular lymphocytes, but not for other leukocytes. This indicates that the effect of interleukin-2 treatment on hepatic (sinusoidal) cells was primarily directed to large granular lymphocytes and Kupffer cells. The large granular lymphocyte accumulation occurred mainly intrasinusoidally, but they were also frequently observed in the space of Disse where they are not found in control rats. This may be explained partly by the observed damage or gaps in the endothelial lining. The intrasinusoidal large granular lymphocytes adhered to the endothelium and to Kupffer cells. Higher responses, for all cell types, were found when interleukin-2 was administered regionally, that is, through the hepatic artery rather than through the systemic route (jugular vein), although the differences were not statistically significant. Doses below 4 x 10(4) U/day did not result in significant increases of large granular lymphocytes in the liver.

Animals↗
PubMed1990

Alterations in Fc receptor activity in sinusoidal endothelial cells and Kupffer cells during D-galactosamine (GalN)-induced liver injury in rats. A histological study.

Fc receptors in sinusoidal cells and immune complex uptake were studied histologically in D-galactosamine HCl (GalN)-induced liver injury in rats. Kupffer cells and monocytes were distinguished from sinusoidal endothelial cells and from each other by endogenous peroxidase staining. Fc receptors were found along the sinusoidal endothelium throughout the lobules in normal livers. In acute injury caused by 300 or 750 mg/kg of GalN, Fc receptors were preserved within necrotic foci until the foci were infiltrated by inflammatory cells. The endothelial Fc receptor activity altered, as demonstrated by their capacity to bind immune complexes, after GalN injection. The activity decreased from 24 h after injection in the periportal areas in both dose groups, and increased transiently with dose-dependence in the remaining areas. Kupffer cell numbers also showed a transient dose-dependent increase, except in the periphery of lobules where they generally decreased. In chronic injury with 400 mg/kg, Fc receptors were lost and Kupffer cells decreased in the periportal areas. Circulating immune complexes were ingested by Kupffer cells and endothelial cells in normal and injured livers, showing the the same distribution as that of Fc receptors except that the complexes decreased gradually towards the centrilobular zones.

Animals↗
PubMed1979

Identification of G6PDH-active sinusoidal cells as Kupffer cells in the rat liver.

The aim of this study was to identify the G6PDH-active sinusoidal cells in the rat liver described by Rieder et al. (1978). Because of their number and distribution in the liver parenchyma, endothelial cells and pit cells could be excluded. Fat-storing cells were specifically marked by vital staining with vitamin A and identified by fluorescence microscopy. Kupffer cells could be detected after vital staining with carmine. Both staining methods allowed a subsequent incubation for the demonstration of G6PDH activity in the same unfixed cryostat section. Whereas more than 80% of the fluorescent particles were found outside the enzyme-positive cells, all G6PDH-active cells contained carmine particles. After counting the G6PDH-active cells, an estimation of 0.217 x 10(8) cells/g liver tissue was obtained. The results indicate that high G6PDH activity is common to all Kupffer cells, and is therefore a highly specific marker enzyme for this class of sinusoidal liver cells.

Animals↗
PubMed1991

Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia.

The objective of this study was to identify the cellular source of the vascular oxidant stress in hepatic ischemia-reperfusion injury in male Fischer rats. Nonparenchymal cells (Kupffer cells, endothelial cells) and neutrophils were isolated from postischemic liver lobes by collagenase-pronase digestion followed by centrifugal elutriation. The spontaneous and stimulated generation of superoxide by these cells were subsequently quantified in vitro. Large Kupffer cells from the postischemic lobes spontaneously generated 300% more superoxide than similar cells from control animals. No difference in spontaneous superoxide formation was found when the small Kupffer cells were compared. No other cells isolated from the postischemic lobes or control liver including neutrophils released any detectable superoxide spontaneously. In contrast, small Kupffer cells and neutrophils from the postischemic liver generated significantly more superoxide after stimulation with phorbol ester or opsonized zymosan than the controls. The considerably higher response with zymosan stimulation compared to phorbol ester indicates a particular priming for a receptor-mediated signal transduction pathway during reperfusion. These studies demonstrate that Kupffer cells are the principal source of the oxidant stress during the initial reperfusion phase after hepatic ischemia. The priming of neutrophils during this time may be an important factor for the later neutrophil-induced injury phase.

Animals↗
PubMed1988

Biphasic control of polymorphonuclear cell migration by Kupffer cells. Effect of exposure to metabolic products of ethanol.

In order to investigate the role of the Kupffer cells in the regulation of the inflammatory reaction seen in alcoholic hepatitis, rat liver Kupffer cells were cultured and exposed to products of ethanol metabolism. The resultant supernatants were tested to study their ability to stimulate or inhibit polymorphonuclear cell chemotaxis. Kupffer cells produced increased chemokinetic activity for human polymorphonuclear leukocytes (84 +/- 6 vs. 61 +/- 4 randomly migrating cells per 5 high power fields; p less than 0.01); when incubated with soluble products of microsomal peroxidation, the Kupffer cells engendered more chemokinetic activity than that produced by untreated Kupffer cells (106 +/- 6 vs. 84 +/- 6 cells per 5 high power fields; p less than 0.05). When Kupffer cells were incubated with acetaldehyde, the chemokinetic activity that appeared in the supernatant did not differ from control (51 +/- 3 vs. 61 +/- 4 randomly migrating cells per 5 high power fields; p = NS). Chemotaxis of polymorphonuclear cells was not observed when the Kupffer cell supernatants were tested by checkerboard analysis. Kupffer cells released a factor which, at different concentrations, inhibited the response of polymorphonuclear cells to the synthetic polypeptide chemotactic factor f-met-leu-phe by 47% (p less than 0.001). This effect was unchanged when the cells were exposed to acetaldehyde or to soluble products of microsomal peroxidation. Our results demonstrate that Kupffer cells are capable of stimulating or inhibiting polymorphonuclear cell chemotaxis and that some of these effects may be influenced by the products of ethanol metabolism, suggesting that Kupffer cells may play an important role in the regulation of the inflammatory reaction seen in alcoholic hepatitis.

Acetaldehyde↗
PubMed1990

High-affinity binding of fibronectin to cultured Kupffer cells.

Hepatic Kupffer cells are a major component of the reticuloendothelial or macrophage system. They were the first phagocytic cell type whose phagocytosis was shown to be influenced by plasma fibronectin, a dimeric opsonic glycoprotein. In the current study, the binding of soluble radioiodinated fibronectin purified from rat serum to isolated rat hepatic Kupffer cells was investigated using a cultured Kupffer cell monolayer technique. Binding was specific, since unlabeled purified fibronectin competed in a dose-dependent manner with the 125I-fibronectin for binding to the Kupffer cells. Addition of gelatin enhanced the binding of 125I-fibronectin to Kupffer cells. The phagocytosis of gelatinized-coated red cells by Kupffer cells was increased either by preopsonizing the target particles with purified fibronectin or by the addition of purified fibronectin to the culture medium. In contrast, exposure of the Kupffer cells to medium containing purified fibronectin followed by wash-removal of the fibronectin did not increase the uptake of gelatin-coated red blood cells, even though fibronectin was detected on the surface of the Kupffer cells by immunofluorescence. Trypsinized monolayers expressed decreased capacity to bind 125I-fibronectin as well as fibronectin-coated sheep erythrocytes. The binding of 125I-fibronectin-gelatin complexes was inhibited by excess unlabeled fibronectin. We calculated that specific high-affinity (Kd = 7.46 x 10(-9) M) binding sites for fibronectin exist on Kupffer cells. There are approximately 2,800-3,500 binding sites or putative "fibronectin receptors" per Kupffer cell. These sites appear to mediate the enhanced phagocytosis of gelatin-coated particles opsonized by fibronectin.

Animals↗
PubMed1990

Monoclonal antibodies to rat Kupffer cells. Anti-KCA-1 distinguishes Kupffer cells from other macrophages.

Two monoclonal antibodies, anti-KCA-1 and anti-KCA-2, directed against rat Kupffer cells (hepatic sinusoidal macrophages) were developed. Immunohistologic studies of the liver and analysis of isolated hepatic cells by immunofluorescence and flow cytometry showed that the reactivity of these antibodies was restricted to macrophages. Both KCA-1+ and KCA-2+ cells were located predominantly in the periportal region; in contrast, Ia+ sinusoidal cells were located primarily in the centrilobular region. Macrophagelike cells within the portal tracts expressed KCA-2 but not KCA-1. These findings indicate the presence of heterogeneity within the macrophage population of the liver. Anti-KCA-1 reactivity appeared to be almost entirely restricted to Kupffer cells; only a few macrophages in the thymus and a small number of cells in the bone marrow expressed KCA-1. In contrast, KCA-2 was more widely distributed; splenic, lymph node, and intestinal macrophages were intensely stained with anti-KCA-2. These studies indicate that KCA-1 is a marker of Kupffer cells.

Animals↗
PubMed1988

Kinetics and parameters of the induction of interleukin 1 secretion by rat Kupffer cells.

Rat Kupffer cells stimulated with bacterial lipopolysaccharide (LPS) produced high levels of interleukin 1 (IL-1), determined by assaying the thymocyte proliferating activity. The unstimulated Kupffer cells secreted no detectable activity. LPS-induced production of IL-1 activity was dose-dependent and as little as 0.1 micrograms/ml of LPS induced the IL-1 production. Thirty minutes were required for LPS to induce sufficient amounts of IL-1 activity. IL-2 activity was not detected in the Kupffer cell culture medium. Another soluble agent, N-acetylmuramyl-L-alanyl-D-isoglutamine, or phagocytable agents, silica and zymosan, also stimulated IL-1 production by Kupffer cells, whereas phorbol myristate acetate did not. Kinetic studies revealed a rapid increase in both intra- and extracellular IL-1 activity within 1 hr following the addition of LPS, with a peak at 6 hr. This IL-1 activity produced by Kupffer cells was heat labile, resistant to freezing and thawing and precipitated with 65% ammonium sulfate. Upon gel filtration, the activity was present in three peaks of approximately 110, 35 and 15 kd. The hepatocyte stimulating activity, when assayed by alpha 2-macroglobulin inducing activity, was detected in the first two peaks but not in the third peak. These studies suggest that LAF activity is distinct from hepatocyte stimulating activity at least in the molecular weight.

Acetylmuramyl-Alanyl-Isoglutamine↗