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1
Haubrich, William S. "Kupffer of Kupffer cells." Gastroenterology 127, no. 1 (July 2004): 16. http://dx.doi.org/10.1053/j.gastro.2004.05.041.
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Karakas, Danielle, June Li, and Heyu Ni. "Novel Mechanisms of Thrombopoietin Generation: The Essential Role of Kupffer Cells." Blood 138, Supplement 1 (November 5, 2021): 3139. http://dx.doi.org/10.1182/blood-2021-145985.
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Abstract Thrombopoietin (TPO) is the physiological regulator of hemopoietic stem cell niche and megakaryocyte differentiation, and therefore platelet production. Prevailing theory posits that TPO is constitutively expressed by hepatocytes, and levels are fine-tuned through platelet and megakaryocyte internalization/clearance via the c-Mpl receptor. Our lab has previously shown that platelet glycoprotein (GP) Ibα is indispensable for platelet-mediated TPO generation (Blood 2018), and recent reports have demonstrated that Kupffer cells, the tissue resident macrophages of the liver, contribute to the clearance of desialylated platelets. However, whether Kupffer cells may contribute to TPO generation has never been explored. To determine the possible role of Kupffer cells in TPO production, clodronate liposome was intravenously administered to deplete Kupffer cells in wild-type mice. Wild-type, Kupffer cell depleted mice showed a TPO decrease of 43.6% (±16%) 2 days post depletion, with only a gradual insignificant increase in TPO levels to day 6. Interestingly, TPO levels could not be significantly increased in wild-type Kupffer cell depleted mice even when transfused 2x10 8 wild-type or desialylated platelets, or 50mU neuraminidase. Kupffer cell depletion in IL4Rα/GPIbα-transgenic mice, which lack platelet-mediated TPO generation, showed a TPO decrease of 22.5% (±5%) from baseline 2 days post depletion, with only a gradual increase in levels to day 6, suggesting that Kupffer cells are required for constitutive in addition to platelet-mediated TPO production. As our lab has previously shown that platelet GPIbα drives platelet-mediated TPO generation, and that Kupffer cells now required, WT and GPIbα -/- platelets were co-cultured with Kupffer cells to assess interaction. Desialylated WT platelets interacted significantly more with Kupffer cells as analyzed by flow cytometry than GPIbα -/- platelets. Interestingly, desialylation of GPIbα -/- platelets did not increase binding to Kupffer cells, consolidating that desialylated GPIbα is required for Kupffer cell interaction, and subsequent TPO generation. This data demonstrates the novel and unexpected finding that Kupffer cells are required for both platelet-mediated and baseline hepatocellular TPO generation. Elucidation of the role of Kupffer cells in this crucial mechanism will provide a better understanding of why thrombocytopenias may occur in pathological states, as well as contribute to the development of TPO mimetic therapies. Disclosures No relevant conflicts of interest to declare.
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Su, Grace L., Sanna M. Goyert, Ming-Hui Fan, Alireza Aminlari, Ke Qin Gong, Richard D. Klein, Andrzej Myc, et al. "Activation of human and mouse Kupffer cells by lipopolysaccharide is mediated by CD14." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 3 (September 1, 2002): G640—G645. http://dx.doi.org/10.1152/ajpgi.00253.2001.
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Upregulation of CD14 in Kupffer cells has been implicated in the pathogenesis of several forms of liver injury, including alcoholic liver disease. However, it remains unclear whether CD14 mediates lipopolysaccharide (LPS) signaling in this specialized liver macrophage population. In this series of experiments, we determined the role of CD14 in LPS activation of Kupffer cells by using several complementary approaches. First, we isolated Kupffer cells from human livers and studied the effects of anti-CD14 antibodies on LPS activation of these cells. Kupffer cells were incubated with increasing concentrations of LPS in the presence and absence of recombinant human LPS binding protein (LBP). With increasing concentrations of LPS, human Kupffer cell tumor necrosis factor-α (TNF-α) production (a marker for Kupffer cell activation) increased in a dose-dependent manner in the presence and absence of LBP. In the presence of anti-human CD14 antibodies, the production of TNF-α was significantly diminished. Second, we compared LPS activation of Kupffer cells isolated from wild-type and CD14 knockout mice. Kupffer cells from CD14 knockout mice produced significantly less TNF-α in response to the same amount of LPS. Together, these data strongly support a critical role for CD14 in Kupffer cell responses to LPS.
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Sakai, Mashito, Ty Dale Troutman, Jason S. Seidman, Zhengyu Ouyang, Nathanael J. Spann, Yohei Abe, Kaori Ego, et al. "Deciphering liver environmental signaling pathways for Kupffer cell identity." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 187.21. http://dx.doi.org/10.4049/jimmunol.202.supp.187.21.
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Abstract Functional specialization of tissue resident macrophages occurs through environmental signals controlling activity and/or expression of transcription factors. Kupffer cells are resident macrophages in the hepatic sinusoids and have critical roles in the innate immune response and iron metabolism. Here, we characterize transcriptomic and epigenetic changes in repopulating liver macrophages following acute Kupffer cell depletion as a means to infer signaling pathways and transcription factors that promote Kupffer cell differentiation. Nr1h3 encoding LXRα is rapidly and highly induced in repopulating liver macrophages, suggesting its induction plays a crucial role in Kupffer cell differentiation. Restricted deletion of Nr1h3 in Kupffer cells reveal that it is required for shaping the Kupffer cell-specific enhancer landscape. Further, we obtain evidence that combinatorial interactions of DLL4 and TGF-β/BMP produced by sinusoidal endothelial cells and endogenous LXR ligands are required for the induction and maintenance of Kupffer cell identity. DLL4 regulation of RBPJ through Notch signaling plays a key role in activating poised enhancers to rapidly induce LXRα and other Kupffer cell lineage-determining factors. These factors in turn reprogram the repopulating liver macrophage enhancer landscape to converge on that of the original resident Kupffer cells. Using molecules which mimic these liver environment signals, we show that it is possible to induce Kupffer cell-specific genes in mouse bone marrow progenitor cells and human monocytes in vitro. Collectively, these findings provide a framework for understanding how macrophage progenitor cells acquire tissue-specific phenotypes.
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Marianneau, Philippe, Anne-Marie Steffan, Cathy Royer, Marie-Thérèse Drouet, D. Jaeck, André Kirn, and Vincent Deubel. "Infection of Primary Cultures of Human Kupffer Cells by Dengue Virus: No Viral Progeny Synthesis, but Cytokine Production Is Evident." Journal of Virology 73, no. 6 (June 1, 1999): 5201–6. http://dx.doi.org/10.1128/jvi.73.6.5201-5206.1999.
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ABSTRACT We investigated the ability of dengue virus to invade human primary Kupffer cells and to complete its life cycle. The virus effectively penetrated Kupffer cells, but the infection did not result in any viral progeny. Dengue virus-replicating Kupffer cells underwent apoptosis and were cleared by phagocytosis. Infected Kupffer cells produced soluble mediators that could intervene in dengue virus pathogenesis.
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MacPhee, P. J., E. E. Schmidt, and A. C. Groom. "Evidence for Kupffer cell migration along liver sinusoids, from high-resolution in vivo microscopy." American Journal of Physiology-Gastrointestinal and Liver Physiology 263, no. 1 (July 1, 1992): G17—G23. http://dx.doi.org/10.1152/ajpgi.1992.263.1.g17.
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Kupffer cells are generally considered fixed tissue macrophages of the liver. However, we have evidence that this opinion is incorrect. High-resolution in vivo video microscopy shows that Kupffer cells have the ability to migrate along sinusoidal walls. Images recorded from anesthetized mice show active locomotion of cells with or against the direction of blood flow or in the absence of flow. The size, changing morphology, and uptake of carbon or microspheres strongly suggest that these are Kupffer cells. Quantitative measurements were made on 29 migrating Kupffer cells. The mean speed of migration was 4.6 +/- 2.6 (SD) microns/min and was not significantly different whether migration occurred with or against the flow. When fluorescent microspheres were given in vivo as a phagocytic challenge, Kupffer cells containing few microspheres migrated more slowly (0.9 +/- 0.9 microns/min, n = 10), whereas those containing many microspheres were never seen to migrate. Individual Kupffer cells were able to move independently, i.e., in directions different from those of neighboring Kupffer cells. These findings may have major implications for the role of Kupffer cells in scavenging foreign particles and as antigen-presenting cells.
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Bilzer, Manfred, Hartmut Jaeschke, Angelika M. Vollmar, Gustav Paumgartner, and Alexander L. Gerbes. "Prevention of Kupffer cell-induced oxidant injury in rat liver by atrial natriuretic peptide." American Journal of Physiology-Gastrointestinal and Liver Physiology 276, no. 5 (May 1, 1999): G1137—G1144. http://dx.doi.org/10.1152/ajpgi.1999.276.5.g1137.
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The generation of reactive oxygen species (ROS) by activated Kupffer cells contributes to liver injury following liver preservation, shock, or endotoxemia. Pharmacological interventions to protect liver cells against this inflammatory response of Kupffer cells have not yet been established. Atrial natriuretic peptide (ANP) protects the liver against ischemia-reperfusion injury, suggesting a possible modulation of Kupffer cell-mediated cytotoxicity. Therefore, we investigated the mechanism of cytoprotection by ANP during Kupffer cell activation in perfused rat livers of male Sprague-Dawley rats. Activation of Kupffer cells by zymosan (150 μg/ml) resulted in considerable cell damage, as assessed by the sinusoidal release of lactate dehydrogenase and purine nucleoside phosphorylase. Cell damage was almost completely prevented by superoxide dismutase (50 U/ml) and catalase (150 U/ml), indicating ROS-related liver injury. ANP (200 nM) reduced Kupffer cell-induced injury via the guanylyl cyclase-coupled A receptor (GCA receptor) and cGMP: mRNA expression of the GCA receptor was found in hepatocytes, endothelial cells, and Kupffer cells, and the cGMP analog 8-bromo-cGMP (8-BrcGMP; 50 μM) was as potent as ANP in protecting from zymosan-induced cell damage. ANP and 8-BrcGMP significantly attenuated the prolonged increase of hepatic vascular resistance when Kupffer cell activation occurred. Furthermore, both compounds reduced oxidative cell damage following infusion of H2O2(500 μM). In contrast, superoxide anion formation of isolated Kupffer cells was not affected by ANP and only moderately reduced by 8-BrcGMP. In conclusion, ANP protects the liver against Kupffer cell-related oxidant stress. This hormonal protection is mediated via the GCA receptor and cGMP, suggesting that the cGMP receptor plays a critical role in controlling oxidative cell damage. Thus ANP signaling should be considered as a new pharmacological target for protecting liver cells against the inflammatory response of activated Kupffer cells without eliminating the vital host defense function of these cells.
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Wang, Fei, Xin Huang, Chun-Shiang Chung, Yaping Chen, Noelle A. Hutchins, and Alfred Ayala. "Contribution of programmed cell death receptor (PD)-1 to Kupffer cell dysfunction in murine polymicrobial sepsis." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 2 (August 1, 2016): G237—G245. http://dx.doi.org/10.1152/ajpgi.00371.2015.
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Recent studies suggest that coinhibitory receptors appear to be important in contributing sepsis-induced immunosuppression. Our laboratory reported that mice deficient in programmed cell death receptor (PD)-1 have increased bacterial clearance and improved survival in experimental sepsis induced by cecal ligation and puncture (CLP). In response to infection, the liver clears the blood of bacteria and produces cytokines. Kupffer cells, the resident macrophages in the liver, are strategically situated to perform the above functions. However, it is not known if PD-1 expression on Kupffer cells is altered by septic stimuli, let alone if PD-1 ligation contributes to the altered microbial handling seen. Here we report that PD-1 is significantly upregulated on Kupffer cells during sepsis. PD-1-deficient septic mouse Kupffer cells displayed markedly enhanced phagocytosis and restoration of the expression of major histocompatibility complex II and CD86, but reduced CD80 expression compared with septic wild-type (WT) mouse Kupffer cells. In response to ex vivo LPS stimulation, the cytokine productive capacity of Kupffer cells derived from PD-1−/− CLP mice exhibited a marked, albeit partial, restoration of the release of IL-6, IL-12, IL-1β, monocyte chemoattractant protein-1, and IL-10 compared with septic WT mouse Kupffer cells. In addition, PD-1 gene deficiency decreased LPS-induced apoptosis of septic Kupffer cells, as indicated by decreased levels of cleaved caspase-3 and reduced terminal deoxynucleotidyl transferase dUTP nick end-labeling-positive cells. Exploring the signal pathways involved, we found that, after ex vivo LPS stimulation, septic PD-1−/− mouse Kupffer cells exhibited an increased Akt phosphorylation and a reduced p38 phosphorylation compared with septic WT mouse Kupffer cells. Together, these results indicate that PD-1 appears to play an important role in regulating the development of Kupffer cell dysfunction seen in sepsis.
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Slevin, Elise, Leonardo Baiocchi, Nan Wu, Burcin Ekser, Keisaku Sato, Emily Lin, Ludovica Ceci, et al. "Kupffer Cells." American Journal of Pathology 190, no. 11 (November 2020): 2185–93. http://dx.doi.org/10.1016/j.ajpath.2020.08.014.
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Ikejima, Kenichi, Nobuyuki Enomoto, Vitor Seabra, Ayako Ikejima, David A. Brenner, and Ronald G. Thurman. "Pronase destroys the lipopolysaccharide receptor CD14 on Kupffer cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 276, no. 3 (March 1, 1999): G591—G598. http://dx.doi.org/10.1152/ajpgi.1999.276.3.g591.
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CD14 is a lipopolysaccharide (LPS) receptor distributed largely in macrophages, monocytes, and neutrophils; however, the role of CD14 in activation of Kupffer cells by LPS remains controversial. The purpose of this study was to determine if different methods used to isolate Kupffer cells affect CD14. Kupffer cells were isolated by collagenase (0.025%) or collagenase-Pronase (0.02%) perfusion and differential centrifugation using Percoll gradients and cultured for 24 h before experiments. CD14 mRNA was detected by RT-PCR from Kupffer cell total RNA as well as from peritoneal macrophages. Western blotting showed that Kupffer cells prepared with collagenase possess CD14; however, it was absent in cells obtained by collagenase-Pronase perfusion. Intracellular calcium in Kupffer cells prepared with collagenase was increased transiently to levels around 300 nM by addition of LPS with 5% rat serum, which contains LPS binding protein. This increase in intracellular calcium was totally serum dependent. Moreover, LPS-induced increases in intracellular calcium in Kupffer cells were blunted significantly (40% of controls) when cells were treated with phosphatidylinositol-specific phospholipase C, which cleaves CD14 from the plasma membrane. However, intracellular calcium did not increase when LPS was added to cells prepared by collagenase-Pronase perfusion even in the presence of serum. These cells were viable, however, because ATP increased intracellular calcium to the same levels as cells prepared with collagenase perfusion. Tumor necrosis factor-α (TNF-α) mRNA was increased in Kupffer cells prepared with collagenase perfusion 1 h after addition of LPS, an effect potentiated over twofold by serum; however, serum did not increase TNF-α mRNA in cells isolated via collagenase-Pronase perfusion. Moreover, treatment with Pronase rapidly decreased CD14 on mouse macrophages (RAW 264.7 cells) and Kupffer cells. These findings indicate that Pronase cleaves CD14 from Kupffer cells, whereas collagenase perfusion does not, providing an explanation for why Kupffer cells do not exhibit a CD14-mediated pathway when prepared with procedures using Pronase. It is concluded that Kupffer cells indeed contain a functional CD14 LPS receptor when prepared gently.
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Thakur, Varsha, Michele T. Pritchard, Megan R. McMullen, and Laura E. Nagy. "Adiponectin normalizes LPS-stimulated TNF-α production by rat Kupffer cells after chronic ethanol feeding." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 5 (May 2006): G998—G1007. http://dx.doi.org/10.1152/ajpgi.00553.2005.
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Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of tumor necrosis factor-α (TNF-α). Adiponectin treatment protects mice from ethanol-induced liver injury. Because adiponectin has anti-inflammatory effects on macrophages, we hypothesized that adiponectin would normalize chronic ethanol-induced sensitization of Kupffer cells to LPS-mediated signals. Serum adiponectin concentrations were decreased by 45% in rats fed an ethanol-containing diet for 4 wk compared with pair-fed rats. Adiponectin dose dependently inhibited LPS-stimulated accumulation of TNF-α mRNA and peptide in Kupffer cells from both pair- and ethanol-fed rats. Kupffer cells from ethanol-fed rats were more sensitive to both globular (gAcrp) and full-length adiponectin (flAcrp) than Kupffer cells from pair-fed controls with suppression at 10 ng/ml adiponectin after chronic ethanol feeding. Kupffer cells expressed both adiponectin receptors 1 and 2; chronic ethanol feeding did not change the expression of adiponectin receptor mRNA or protein. gAcrp suppressed LPS-stimulated ERK1/2 and p38 phosphorylation as well as IκB degradation at 100–1,000 ng/ml in Kupffer cells from both pair- and ethanol-fed rats. However, only LPS-stimulated ERK1/2 phosphorylation was sensitive to 10 ng/ml gAcrp. gAcrp also normalized LPS-stimulated DNA binding activity of early growth response-1 with greater sensitivity in Kupffer cells from rats fed chronic ethanol. In conclusion, these results demonstrate that Kupffer cells from ethanol-fed rats are more sensitive to the anti-inflammatory effects of both gAcrp and flAcrp. Suppression of LPS-stimulated ERK1/2 signaling by low concentrations of gAcrp was associated with normalization of TNF-α production by Kupffer cells after chronic ethanol exposure.
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Kamps, J. A. A. M., J. K. Kruijt, J. Kuiper, and T. J. C. Van Berkel. "Uptake and degradation of human low-density lipoprotein by human liver parenchymal and Kupffer cells in culture." Biochemical Journal 276, no. 1 (May 15, 1991): 135–40. http://dx.doi.org/10.1042/bj2760135.
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The association with and degradation by cultured human parenchymal liver cells and human Kupffer cells of human low-density lipoprotein (LDL) was investigated in order to define, for the human situation, the relative abilities of the various liver cell types to interact with LDL. With both human parenchymal liver cells and Kupffer cells the association of LDL with the cells followed saturation kinetics which were coupled to LDL degradation. The association of LDL (per mg of cell protein) to both cell types was comparable, but the association with human Kupffer cells was much more efficiently coupled to degradation than was the case in parenchymal cells. The capacity of human Kupffer cells to degrade LDL was consequently 18-fold higher (per mg of cell protein) than that of the human parenchymal liver cells. Competition studies showed that unlabelled LDL competed efficiently with the cell association and degradation of 125I-labelled LDL with both parenchymal and Kupffer cells, while unlabelled acetyl-LDL was ineffective. The degradation of LDL by parenchymal and Kupffer cells was blocked by chloroquine and NH4Cl, indicating that it occurs in the lysosomes. Binding and degradation of LDL by human liver parenchymal cells and human Kupffer cells appeared to be completely calcium-dependent. It is concluded that the association and degradation of LDL by human Kupffer and parenchymal liver cells proceeds through the specific LDL receptor, whereas the association of LDL to Kupffer cells is more efficiently coupled to degradation. The presence of the highly active LDL receptor on human Kupffer cells might contribute significantly to LDL catabolism by human liver, especially under conditions whereby the LDL receptor on parenchymal cells is down-regulated.
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Cha, Sung-Jae, Kyle Jarrod McLean, and Marcelo Jacobs-Lorena. "Identification of Plasmodium GAPDH epitopes for generation of antibodies that inhibit malaria infection." Life Science Alliance 1, no. 5 (September 18, 2018): e201800111. http://dx.doi.org/10.26508/lsa.201800111.
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Plasmodium sporozoite liver infection is an essential step for parasite development in its mammalian host. Previously, we used a phage display library to identify mimotope peptides that bind to Kupffer cells and competitively inhibit sporozoite–Kupffer cell interaction. These peptides led to the identification of a Kupffer cell receptor—CD68—and a Plasmodium sporozoite ligand—GAPDH—that are required for sporozoite traversal of Kupffer cells and subsequent infection of hepatocytes. Here, we report that the C-terminal end of Plasmodium GAPDH interacts with the Kupffer CD68 receptor, and identify two epitopes within this region as candidate antigens for the development of antibodies that inhibit Plasmodium infection.
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Elbakidze, G. M. "MECHANISMS OF PROTECTIVE INFLUENCE OF ENDOTOXIN-ACTIVATED KUPFFER CELLS ON HEPATOCYTES." Annals of the Russian academy of medical sciences 67, no. 5 (May 23, 2012): 48–54. http://dx.doi.org/10.15690/vramn.v67i5.274.
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Various aspects of protective and damaging influences of endotoxin-activated Kupffer cells on hepatocytes are discussed. Requests for protective subcellular mechanism activated by Kupffer cells mediators were formulated. Two possible mechanisms of activated Kupffer cells protective influence on hepatocytes which satisfy these requests are considered. One of them may operate via hepatocyte non-specific reaction to damage initiated by Kupffer cells mediators. Another one may work through activation of endotoxin-dependent tissue stress mechanism in hepatocytes. The data confirm the development of non-specific reaction to damage and the mechanism of tissue stress realized by means of tissue-specific effector in hepatocytes under endotoxin-activated Kupffer cells influence.
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Thandi, Ramya Sivangala, Deepak Tripathi, Rajesh Kumar Radhakrishnan, Padmaja Paidipally, and Ramakrishna Vankayalapati. "Kupffer cells restricts Mycobacterium tuberculosis growth better than alveolar macrophages." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 173.20. http://dx.doi.org/10.4049/jimmunol.200.supp.173.20.
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Abstract Kupffer cells protect liver from bacterial infections. In the current study, we compared Mycobacterium tuberculosis (M.tb) growth and cytokine production by mice kupffer cells and alveolar macrophages. M.tb H37Rv infected kupffer cells and alveolar macrophages produced equal amounts of TNF-α, IL-6, IL-10 & IL-1β. In contrast, kupffer cells restricted M.tb growth better than alveolar macrophages (1 ± 0.346×106 CFU vs. 4 ± 0.916×106 CFU, p<0.03). There is no significant difference in the apoptosis of M.tb infected kupffer cells and alveolar macrophages. In contrast, M.tb infected kupffer cells expressed significant higher amounts of autophagy molecules LC-3B, ATG-7, ATG-5 and Beclin-1 (p<0.005, p<0.002, p<0.0032 & p<0.004 respectively) compared to M.tb infected alveolar macrophages as determined by real-time PCR. This was confirmed by Western blot and confocal microscopy. Our results suggest autophagy is involved in better restriction of M.tb growth by kupffer cells. Prime PCR analysis for 35 intracelluar signaling molecules those are involved in autophagy as well as in cytoskeleton indicated that M.tb infected kupffer cells significantly express higher levels of VASP (Vasodilator-stimulated phosphoprotein), RhoA (Ras homolog gene family member A) and Arp3 (Actin–related protein 3) genes (two fold, p<0.01, p<0.02&p<0.02 respectively) compared to M.tb infected alveolar macrophages. Studies are underway 1. To confirm whether autophagy is involved in better restriction of M.tb growth in kupffer cells. 2. Determine the role of cytoskeleton proteins those are involved in enhanced autophagy and M.tb growth inhibition in kupffer cells. 3. Determining in vivo relevance to our current findings using mouse model of M.tb infection.
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Cubero, Francisco Javier, and Natalia Nieto. "Arachidonic acid stimulates TNFα production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 2 (July 15, 2012): G228—G239. http://dx.doi.org/10.1152/ajpgi.00465.2011.
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Kupffer cells are a key source of mediators of alcohol-induced liver damage such as reactive oxygen species, chemokines, growth factors, and eicosanoids. Since diets rich in polyunsaturated fatty acids are a requirement for the development of alcoholic liver disease, we hypothesized that polyunsaturated fatty acids could synergize with ethanol to promote Kupffer cell activation and TNFα production, hence, contributing to liver injury. Primary Kupffer cells from control and from ethanol-fed rats incubated with arachidonic acid showed similar proliferation rates than nontreated cells; however, arachidonic acid induced phenotypic changes, lipid peroxidation, hydroperoxides, and superoxide radical generation. Similar effects occurred in human Kupffer cells. These events were greater in Kupffer cells from ethanol-fed rats, and antioxidants and inhibitors of arachidonic acid metabolism prevented them. Arachidonic acid treatment increased NADPH oxidase activity. Inhibitors of NADPH oxidase and of arachidonic acid metabolism partially prevented the increase in oxidant stress. Upon arachidonic acid stimulation, there was a rapid and sustained increase in TNFα, which was greater in Kupffer cells from ethanol-fed rats than in Kupffer cells from control rats. Arachidonic acid induced ERK1/2 phosphorylation and nuclear translocation of early growth response-1 (Egr1), and ethanol synergized with arachidonic acid to promote this effect. PD98059, a mitogen extracellular kinase 1/2 inhibitor, and curcumin, an Egr1 inhibitor, blocked the arachidonic acid-mediated upregulation of TNFα in Kupffer cells. This study unveils the mechanism whereby arachidonic acid and ethanol increase TNFα production in Kupffer cells, thus contributing to alcoholic liver disease.
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Schemmer, Peter, Nobuyuki Enomoto, Blair U. Bradford, Hartwig Bunzendahl, James A. Raleigh, John J. Lemasters, and Ronald G. Thurman. "Activated Kupffer cells cause a hypermetabolic state after gentle in situ manipulation of liver in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 6 (June 1, 2001): G1076—G1082. http://dx.doi.org/10.1152/ajpgi.2001.280.6.g1076.
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Harvesting trauma to the graft dramatically decreases survival after liver transplantation. Since activated Kupffer cells play a role in primary nonfunction, the purpose of this study was to test the hypothesis that organ manipulation activates Kupffer cells. To mimic what occurs with donor hepatectomy, livers from Sprague-Dawley rats underwent dissection with or without gentle organ manipulation in a standardized manner in situ. Perfused livers exhibited normal values for O2 uptake (105 ± 5 μmol · g−1 · h−1) measured polarigraphically; however, 2 h after organ manipulation, values increased significantly to 160 ± 8 μmol · g−1 · h−1 and binding of pimonidazole, a hypoxia marker, increased about threefold ( P < 0.05). Moreover, Kupffer cells from manipulated livers produced three- to fourfold more tumor necrosis factor-α and PGE2, whereas intracellular calcium concentration increased twofold after lipopolysaccharide compared with unmanipulated controls ( P < 0.05). Gadolinium chloride and glycine prevented both activation of Kupffer cells and effects of organ manipulation. Furthermore, indomethacin given 1 h before manipulation prevented the hypermetabolic state, hypoxia, depletion of glycogen, and release of PGE2 from Kupffer cells. These data indicate that gentle organ manipulation during surgery activates Kupffer cells, leading to metabolic changes dependent on PGE2 from Kupffer cells, which most likely impairs liver function. Thus modulation of Kupffer cell function before organ harvest could be beneficial in human liver transplantation and surgery.
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Cha, Sung-Jae, Kiwon Park, Prakash Srinivasan, Christian W. Schindler, Nico van Rooijen, Monique Stins, and Marcelo Jacobs-Lorena. "CD68 acts as a major gateway for malaria sporozoite liver infection." Journal of Experimental Medicine 212, no. 9 (July 27, 2015): 1391–403. http://dx.doi.org/10.1084/jem.20110575.
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After being delivered by the bite from an infected mosquito, Plasmodium sporozoites enter the blood circulation and infect the liver. Previous evidence suggests that Kupffer cells, a macrophage-like component of the liver blood vessel lining, are traversed by sporozoites to initiate liver invasion. However, the molecular determinants of sporozoite–Kupffer cell interactions are unknown. Understanding the molecular basis for this specific recognition may lead to novel therapeutic strategies to control malaria. Using a phage display library screen, we identified a peptide, P39, that strongly binds to the Kupffer cell surface and, importantly, inhibits sporozoite Kupffer cell entry. Furthermore, we determined that P39 binds to CD68, a putative receptor for sporozoite invasion of Kupffer cells that acts as a gateway for malaria infection of the liver.
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Lichtman, Steven N., Jian Wang, and John J. Lemasters. "LPS receptor CD14 participates in release of TNF-α in RAW 264.7 and peritoneal cells but not in Kupffer cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 275, no. 1 (July 1, 1998): G39—G46. http://dx.doi.org/10.1152/ajpgi.1998.275.1.g39.
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Lipopolysaccharide (LPS) is a bacterial polymer that stimulates macrophages to release tumor necrosis factor-α (TNF-α). In macrophages (RAW 264.7 and peritoneal cells), LPS binds to the CD14 surface receptor as the first step toward signaling. Liver macrophages, Kupffer cells, are the most numerous fixed-tissue macrophage in the body. The presence of CD14 on Kupffer cells and its role in LPS stimulation of TNF-α were examined. TNF-α release by Kupffer cells after LPS stimulation was the same in the presence and absence of serum. RAW 264.7 and peritoneal cells, which utilize the CD14 receptor, released significantly less TNF-α after LPS stimulation in the absence of serum because of the absence of LPS-binding protein. Phosphatidylinositol-phospholipase C treatment, which cleaves the CD14 receptor, decreased LPS-stimulated TNF-α release by RAW 264.7 cells but not by Kupffer cells. Deacylated LPS (dLPS) competes with LPS at the CD14 receptor when incubated in a ratio of 100:1 (dLPS/LPS). Such competition blocked LPS-stimulated TNF-α release from RAW 264.7 cells but not from Kupffer cells. Western and fluorescence-activated cell sorter analysis directly demonstrated the presence of CD14 on RAW 264.7 cells and murine peritoneal cells but showed only minimal amounts of CD14 in murine Kupffer cells. LPS stimulation did not increase the amount of CD14 detectable on mouse Kupffer cells. CD14 expression is very low in Kupffer cells, and LPS-stimulated TNF-α release is independent of CD14 in these cells.
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Campion, Sarah N., Rachel Johnson, Lauren M. Aleksunes, Michael J. Goedken, Nico van Rooijen, George L. Scheffer, Nathan J. Cherrington, and José E. Manautou. "Hepatic Mrp4 induction following acetaminophen exposure is dependent on Kupffer cell function." American Journal of Physiology-Gastrointestinal and Liver Physiology 295, no. 2 (August 2008): G294—G304. http://dx.doi.org/10.1152/ajpgi.00541.2007.
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During acetaminophen (APAP) hepatotoxicity, increased expression of multidrug resistance-associated proteins 2, 3, and 4 (Mrp2-4) occurs. Mrp4 is the most significantly upregulated transporter in mouse liver following APAP treatment. Although the expression profiles of liver transporters following APAP hepatotoxicity are well characterized, the regulatory mechanisms contributing to these changes remain unknown. We hypothesized that Kupffer cell-derived mediators participate in the regulation of hepatic transporters during APAP toxicity. To investigate this, C57BL/6J mice were pretreated with clodronate liposomes (0.1 ml iv) to deplete Kupffer cells and then challenged with APAP (500 mg/kg ip). Liver injury was assessed by plasma alanine aminotransferase and hepatic transporter protein expression was determined by Western blot and immunohistochemistry. Depletion of Kupffer cells by liposomal clodronate increased susceptibility to APAP hepatotoxicity. Although increased expression of several efflux transporters was observed after APAP exposure, only Mrp4 was found to be differentially regulated following Kupffer cell depletion. At 48 and 72 h after APAP dosing, Mrp4 levels were increased by 10- and 33-fold, respectively, in mice receiving empty liposomes. Immunohistochemistry revealed Mrp4 staining confined to centrilobular hepatocytes. Remarkably, Kupffer cell depletion completely prevented Mrp4 induction by APAP. Elevated plasma levels of TNF-α and IL-1β were also prevented by Kupffer cell depletion. These findings show that Kupffer cells protect the liver from APAP toxicity and that Kupffer cell mediators released in response to APAP are likely responsible for the induction of Mrp4.
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Froh, Matthias, Ronald G. Thurman, and Michael D. Wheeler. "Molecular evidence for a glycine-gated chloride channel in macrophages and leukocytes." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 4 (October 1, 2002): G856—G863. http://dx.doi.org/10.1152/ajpgi.00503.2001.
Full textAbstract:
Recent studies have demonstrated that glycine blunts the response of Kupffer cells to endotoxin. Based on pharmacological evidence, it was hypothesized that Kupffer cells and other macrophages contain a glycine-gated chloride channel similar to the glycine receptor expressed in neuronal tissues. Moreover, glycine stimulates influx of radiolabeled chloride in Kupffer cells in a dose-dependent manner. RT-PCR was used to identify mRNA of both α- and β-subunits of the glycine receptor in rat Kupffer cells, peritoneal neutrophils, and splenic and alveolar macrophages, similar to the sequence generated from rat spinal cord. Importantly, the sequence of the cloned Kupffer cell glycine receptor fragment for the β-subunit was >95% homologous with the receptor from the spinal cord. Membranes of these cells also contain a protein that is immunoreactive with antibodies against the glycine-gated chloride channel. These data demonstrate that Kupffer cells, as well as other macrophages and leukocytes, express mRNA and protein for a glycine-gated chloride channel with both molecular and pharmacological properties similar to the channel expressed in the central nervous system.
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SCHREIBER, Rainer, Fan ZHANG, and Dieter HÄUSSINGER. "Regulation of vesicular pH in liver macrophages and parenchymal cells by ammonia and anisotonicity as assessed by fluorescein isothiocyanate-dextran fluorescence." Biochemical Journal 315, no. 2 (April 15, 1996): 385–92. http://dx.doi.org/10.1042/bj3150385.
Full textAbstract:
Short-term-cultivated rat hepatocytes and Kupffer cells were allowed to endocytose fluorescein isothiocyanate (FITC)-coupled dextran, in order to study the effects of aniso-osmotic exposure and NH4Cl on apparent vesicular pH (pHves) by single-cell fluorescence. Following a 2 h loading period with FITC–dextran in normo-osmotic (305 mosmol/l) medium, the apparent pHves was 6.01±0.05 (n = 39) in parenchymal cells and 4.94±0.04 (n = 76) in Kupffer cells. Under these conditions pHves in parenchymal cells, but not in Kupffer cells, was sensitive to changes in ambient osmolarity. Inhibition of vacuolar H+-ATPase by concanamycin A did not affect the osmosensitivity of pHves in parenchymal cells. However, the effects of anisotonicity on pHves were largely abolished in the presence of 4,4´-di-isothiocyanato-stilbene-2,2´-disulphonic acid (DIDS) or when extracellular chloride was substituted for gluconate. In neither Kupffer cells, nor liver parenchymal cells did hypo-osmotic cell swelling cause an increase in intracellular Ca2+. With regard to vesicular acidification, the following differences were noted between parenchymal and Kupffer cells. (1) In Kupffer cells endocytosed FITC–dextran reached a strongly acidic compartment with a pH value of approx. 5 within 5 min, whereas it took 4–5 h in parenchymal cells. Modification of pHves by hypo-osmolarity in Kupffer cells was only observed in a short-lived ‘early’ compartment with a pH value of approx. 6. (2) In contrast to pHves in parenchymal cells, pHves in Kupffer cells was very sensitive towards alkalinization by NH4Cl: addition of NH4Cl at 1 or 10 mM increased apparent pHves by 0.80 or 1.46 in Kupffer cells, but only by 0.18 or 0.56 in parenchymal cells. The low ammonia sensitivity of pHves in parenchymal cells was observed not only in the less acidic (pH approx. 6) endocytotic compartment which is reached by FITC–dextran within 2 h, but also in the stronger acidic compartment (pH approx. 5) which is reached after 4–5 h. (3) NH4Cl had no effect on the osmosensitivity of pHves in parenchymal cells, whereas in Kupffer cells pHves became sensitive to anisotonicity when NH4Cl was present. Osmosensitivity of pHves in Kupffer cells under these conditions, however, was not affected by genistein, DIDS or colchicine, whereas these compounds abolished the osmosensitivity of pHves in parenchymal cells. It is suggested that regulation of pHves by cell volume in liver parenchymal cells involves changes of vesicular chloride conductance. In addition, there are marked differences between Kupffer and parenchymal cells with respect to vesicular ammonia permeability and the kinetics of endocytotic membrane flow and acidification.
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Troutman, Ty Dale, Jason S. Seidman, Mashito Sakai, Anita Gola, Zhengyu Ouyang, Nathanael J. Spann, Cassi M. Bruni, et al. "Exploiting altered enhancer landscapes to decode pathogenic changes in gene expression of diverse hepatic macrophages." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 59.2. http://dx.doi.org/10.4049/jimmunol.202.supp.59.2.
Full textAbstract:
Abstract Kupffer cells have specialized roles supporting the environment of the liver during homeostasis and disease. However, the key regulatory elements governing these behaviors are unknown. Using scRNA-seq, we found diversification of Kupffer cells and recruitment of additional macrophage subtypes during nonalcoholic steatohepatitis (NASH). A significant source of macrophage heterogeneity during NASH was traced to Cx3cr1 expressing monocytes. Further, macrophage subsets were localized in distinct niches, suggesting environmental specification as a key determinant of macrophage heterogeneity. We profiled chromatin accessibility of the major NASH associated macrophage populations to identify transcription factors governing their environmental specification. These results predict greater NFκB, RUNX, and AP1 activity in recruited hepatic macrophages compared to Kupffer cells. Surprisingly, we found minimal significant chromatin accessibility changes comparing Kupffer cells from healthy mice to mice with NASH, even though several thousand genes were differentially expressed. Instead, NASH led to altered chromatin activity, as measured by H3K27ac ChIP-seq, at Kupffer cell enhancer regions. A binding element for LXR (liver X receptor) was the top transcription factor motif identified in Kupffer cell enhancers with reduced activity during NASH. Furthermore, LXRα was required to maintain expression of a unique gene signature defining healthy Kupffer cells. Thus, our studies establish for the first time gene regulatory events controlling diverse hepatic macrophages during homeostasis and NASH.
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Maruiwa, M., A. Mizoguchi, G. J. Russell, N. Narula, M. Stronska, E. Mizoguchi, H. Rabb, M. A. Arnaout, and A. K. Bhan. "Anti-KCA-3, a monoclonal antibody reactive with a rat complement C3 receptor, distinguishes Kupffer cells from other macrophages." Journal of Immunology 150, no. 9 (May 1, 1993): 4019–30. http://dx.doi.org/10.4049/jimmunol.150.9.4019.
Full textAbstract:
Abstract A new mAb, designated anti-KCA-3, was developed against rat Kupffer cells. The reactivity of anti-KCA-3 was restricted to macrophages with preferential binding to Kupffer cells; only a few macrophages in the spleen, lymph nodes, lungs, and intestine stained with the antibody. A very small number of peritoneal resident and exudate macrophages reacted with the antibody and no reactivity was seen within the thymus, skin, heart, kidneys, brain, peripheral blood, and bone marrow. KCA-3 was expressed predominantly by the Kupffer cells in the periportal region rather than in the centrilobular region of the hepatic lobules. The cells in the portal tract did not stain with the antibody. The staining of the cytosmears and FACS analysis of the Kupffer cell fraction isolated from hepatic sinusoidal cells by centrifugal elutriation revealed that as many as 62% and 49% of the cells were stained with anti-KCA-3, respectively. Immunoelectron microscopic study of the liver indicated that expression of KCA-3 on Kupffer cells was limited to the plasma membrane facing the sinusoid rather than the space of Disse. Immunoprecipitation and SDS-PAGE analysis demonstrated KCA-3 to have a m.w. of approximately 50 kDa under both reducing and nonreducing conditions. After treatment of KCA-3 with N-glycanase, there was no significant change in the m.w., indicating KCA-3 was not highly glycosylated. C3b- and iC3b-mediated rosette formation between Kupffer cells and sensitized SRBC was inhibited by the antibody, implying that KCA-3 functioned as a complement C3 receptor or complement receptor-associated molecule. Furthermore, KCA-3 was eluted from C3b-Sepharose but not HSA-Sepharose after incubation with Kupffer cell lysate, indicating that KCA-3 directly binds C3b. The cell distribution, ligand-binding specificity, and biochemical properties of the protein were found to be different from the complement C3 receptors previously described. Because OX42 (antibody reactive with the rat CR3 receptor) inhibited complement C3-mediated rosette formation with peritoneal resident macrophages but not with Kupffer cells, the findings suggest that C3-mediated binding to Kupffer cells and to peritoneal macrophages is mediated by two different receptors. We conclude that anti-KCA-3 recognizes a novel type of complement C3 receptor preferentially expressed on Kupffer cells.
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Nukina, S., T. Fusaoka, and R. G. Thurman. "Glycogenolytic effect of adenosine involves ATP from hepatocytes and eicosanoids from Kupffer cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 266, no. 1 (January 1, 1994): G99—G105. http://dx.doi.org/10.1152/ajpgi.1994.266.1.g99.
Full textAbstract:
In the perfused liver, infusion of adenosine (50 microM) caused an increase in portal pressure and glucose output as well as a brief increase in oxygen uptake followed by a transient decrease within 1 min. Half-maximal glycogenolytic effect was observed with approximately 20 microM adenosine, and the stimulation was maximal at concentrations > 50 microM. The effect of adenosine was blocked when Kupffer cells were destroyed with gadolinium chloride treatment (10 mg/kg iv), supporting the hypothesis that eicosanoid release from Kupffer cells participates in the effect of adenosine in the liver. Although adenosine has been reported to increase eicosanoid release from perfused liver (S. vom Dahl, M. Wettstein, W. Gerok, and D. Hussinger, Biochem. J. 270: 39-44, 1990), in this study adenosine failed to stimulate prostaglandin release from cultured Kupffer cells at concentrations ranging from 1 microM to 1 mM, casting doubt on the hypothesis that Kupffer cells are totally responsible for the effect of adenosine. In contrast, adenosine increased ATP transiently from 4 to 15 nM in effluent from perfused livers concomitant with a transient increase in carbohydrate output and portal pressure. To assess which type of hepatic cells released ATP after addition of adenosine, parenchymal, Kupffer, and endothelial cells were isolated and incubated with adenosine. Adenosine increased ATP concentrations in culture media of parenchymal cells but not from Kupffer or endothelial cells. Furthermore, ATP stimulated prostaglandin release from cultured Kupffer cells, whereas ATP (10 microM) infusion caused glucose release with kinetics similar to adenosine in perfused livers, an effect that was blocked by destroying Kupffer cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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Kuiper, J., H. F. Bakkeren, E. A. Biessen, and T. J. Van Berkel. "Characterization of the interaction of galactose-exposing particles with rat Kupffer cells." Biochemical Journal 299, no. 1 (April 1, 1994): 285–90. http://dx.doi.org/10.1042/bj2990285.
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The characteristics of the recognition system involved in the binding of galactose-exposing particles to freshly isolated rat Kupffer cells were determined. For this purpose we used iodinated lactosylated low-density lipoprotein (125I-Lac-LDL) as a ligand for the galactose receptor on Kupffer cells. The affinity of the binding of 125I-Lac-LDL to Kupffer cells was saturable (23,500 galactose-specific binding sites per cell) and of high affinity (2.4 +/- 0.3 nM). The order of potency of various carbohydrates in inhibiting the association of 125I-Lac-LDL with Kupffer cells was as follows: N-acetylgalactosamine > L-fucose >> N-acetylglucosamine/mannan. Association of 125I-Lac-LDL with Kupffer cells in the absence of Ca2+ was at the same level as in the presence of 50 mM N-acetylgalactosamine. A polyclonal antibody raised against the rat asialoglycoprotein receptor inhibited the binding of 125I-Lac-LDL to Kupffer cells and reacted in a Western blot with two proteins (molecular mass 88 and 77 kDa), which correspond to the molecular mass of the fucose receptor [Lehrman, Haltiwanger and Hill (1986) J. Biol. Chem. 261, 7426-7432]. Furthermore, the ability of fucosylated neoglycoproteins to displace 125I-Lac-LDL from Kupffer cells was equally dependent on the extent of fucosylation as previously reported for the fucose receptor. We conclude that the fucose receptor and not the C-reactive protein, as recently proposed [Kempka, Roos and Kolb-Bachofen (1990) J. Immunol. 144, 1004-1009], functions as the galactose-particle receptor on the Kupffer cell. The binding of galactose-exposing particles to the fucose receptor is a previously unknown property of this receptor.
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Gregory, Stephen H., Edward J. Wing, Kristine L. Danowski, Nico van Rooijen, Kevin F. Dyer, and David J. Tweardy. "IL-6 Produced by Kupffer Cells Induces STAT Protein Activation in Hepatocytes Early During the Course of Systemic Listerial Infections." Journal of Immunology 160, no. 12 (June 15, 1998): 6056–61. http://dx.doi.org/10.4049/jimmunol.160.12.6056.
Full textAbstract:
Abstract Kupffer cells were the principal source of IL-6 produced in the livers of mice following i.v. inoculation of Listeria monocytogenes. IL-6 mRNA expression and the production of IL-6 were reduced drastically within the nonparenchymal liver cell population derived from mice rendered Kupffer cell depleted by pretreatment with liposome-encapsulated dichloromethylene diphosphonate. A sharp increase in the appearance of activated STAT3 occurred in extracts of purified hepatocytes derived from normal mice infected i.v. with Listeria. Remarkably, the kinetics of this increase overlapped IL-6 mRNA expression by Kupffer cells; each peaked at approximately 30 min postinfection. No increase in STAT3 activation was observed in IL-6-deficient or Kupffer cell-depleted animals. The results of these experiments indicate that the synthesis of IL-6 and the activation of STAT3 within hepatocytes are critical functions of Kupffer cells occurring very early during the course of systemic listerial infections.
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Li, Chen, Jing-Yong Xu, and Yuan Liu. "Sonazoid-enhanced ultrasonography and pathologic characters of CD68 positive cell in primary hepatic perivascular epithelioid cell tumors: A case report and literature review." Open Medicine 16, no. 1 (January 1, 2021): 737–41. http://dx.doi.org/10.1515/med-2021-0275.
Full textAbstract:
Abstract Perivascular epithelioid cell tumor (PEComa) is a mesenchymal tumor rarely described in the liver. Sonazoid is a new ultrasound contrast with both vascular and post-vascular phases due to the uptake of Kupffer cell. CD68 is a defined immunohistorical staining marker for macrophage including Kupffer cell. No previous cases have been reported to reveal Kupffer images in the post-vascular phase by using Sonazoid and pathologic characters of CD68 positive cell in PEComa. Herein, we describe the first case to present Sonazoid contrast-enhanced ultrasonography (CEUS) findings in Kupffer images and CD68 positive cell in hepatic PEComa which may lead to rethink of the phagocytic properties of macrophages.
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Tan, Quanhui, Jianjun Hu, Xiaolan Yu, Wen Guan, Huili Lu, Yan Yu, Yongsheng Yu, Guoqiang Zang, and Zhenghao Tang. "The Role of IL-1 Family Members and Kupffer Cells in Liver Regeneration." BioMed Research International 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/6495793.
Full textAbstract:
Interleukin-1 (IL-1) family and Kupffer cells are linked with liver regeneration, but their precise roles remain unclear. IL-1 family members are pleiotropic factors with a range of biological roles in liver diseases, inducing hepatitis, cirrhosis, and hepatocellular carcinoma, as well as liver regeneration. Kupffer cells are the main source of IL-1 and IL-1 receptor antagonist (IL-1Ra), the key members of IL-1 family. This systemic review highlights a close association of IL-1 family members and Kupffer cells with liver regeneration, although their specific roles are inconclusive. Moreover, IL-1 members are proposed to induce effects on liver regeneration through Kupffer cells.
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van Oosten, Marijke, Erika van de Bilt, Theo J. C. van Berkel, and Johan Kuiper. "New Scavenger Receptor-Like Receptors for the Binding of Lipopolysaccharide to Liver Endothelial and Kupffer Cells." Infection and Immunity 66, no. 11 (November 1, 1998): 5107–12. http://dx.doi.org/10.1128/iai.66.11.5107-5112.1998.
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ABSTRACT Lipopolysaccharide (LPS) is cleared from the blood mainly by the liver. The Kupffer cells are primarily responsible for this clearance; liver endothelial and parenchymal cells contribute to a lesser extent. Although several binding sites have been described, only CD14 is known to be involved in LPS signalling. Among the other LPS binding sites that have been identified are scavenger receptors. Scavenger receptor class A (SR-A) types I and II are expressed in the liver on endothelial cells and Kupffer cells, and a 95-kDa receptor, identified as macrosialin, is expressed on Kupffer cells. In this study, we examined the role of scavenger receptors in the binding of LPS by the liver in vivo and in vitro. Fucoidin, a scavenger receptor ligand, significantly reduced the clearance of 125I-LPS from the serum and decreased the liver uptake of 125I-LPS about 40%. Within the liver, the in vivo binding of 125I-LPS to Kupffer and liver endothelial cells was decreased 72 and 71%, respectively, while the binding of 125I-LPS to liver parenchymal cells increased 34% upon fucoidin preinjection. Poly(I) inhibited the binding of 125I-LPS to Kupffer and endothelial cells in vitro 73 and 78%, respectively, while poly(A) had no effect. LPS inhibited the binding of acetylated low-density lipoprotein (acLDL) to Kupffer and liver endothelial cells 40 and 55%, respectively, and the binding of oxidized LDL (oxLDL) to Kupffer and liver endothelial cells 65 and 61%, respectively. oxLDL and acLDL did not significantly inhibit the binding of LPS to these cells. We conclude that on both endothelial cells and Kupffer cells, LPS binds mainly to scavenger receptors, but SR-A and macrosialin contribute to a limited extent to the binding of LPS.
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Spolarics, Zoltán, and Jun-Xi Wu. "Role of glutathione and catalase in H2O2detoxification in LPS-activated hepatic endothelial and Kupffer cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 273, no. 6 (December 1, 1997): G1304—G1311. http://dx.doi.org/10.1152/ajpgi.1997.273.6.g1304.
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The present study investigated the effect of lipopolysaccharide (LPS; from Escherichia coli, 2 mg/kg body wt ip) on selected aspects of the antioxidant status in Kupffer and sinusoidal endothelial cells. Cells were isolated 18 h after the injection of saline or LPS. In fresh suspension cultures, cellular reduced glutathione (GSH) and H2O2were determined by monochlorobimane, and 2′,7′-dichlorofluorescein diacetate, respectively, using a fluorescence plate reader. LPS injection increased GSH content two- to threefold in Kupffer cells compared with cells from control rats. Cellular GSH content was higher in endothelial than Kupffer cells. However, LPS did not increase GSH content in endothelial cells. Addition of H2O2(40–200 μM) to Kupffer or endothelial cells caused a transient decrease in GSH, which was more pronounced in cells from control rats (∼45% drop) than in LPS-exposed cells (∼25% drop). Depleted GSH levels were accompanied by a proportional increase in cellular H2O2. After inhibition of catalase by 3-amino-1,2,4-triazole, the presence of 0.2 mM H2O2depleted GSH content by 75% and 40% in Kupffer cells from saline- or LPS-injected rats, respectively. The same treatments caused a similar 50% decrease in both activated and control endothelial cells. LPS decreased catalase activity by 45% in Kupffer cells, whereas it had no effect on catalase in endothelial cells. Glutathione reductase activity was not altered by LPS in either cell type. These data show that in activated Kupffer cells the elevated level of cellular glutathione plays an augmented role in the protection against reactive oxygen species, whereas the contribution of catalase to H2O2detoxification is attenuated. In LPS-stimulated endothelial and Kupffer cells, the efficient maintenance of GSH is consistent with upregulated production of reducing power through the hexose phosphate shunt observed previously.
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Towner, Rheal A., Lester A. Reinke, Edward G. Janzen, and Shigeto Yamashiro. "In vivo magnetic resonance imaging study of Kupffer cell involvement in CCl4-induced hepatotoxicity in rats." Canadian Journal of Physiology and Pharmacology 72, no. 5 (May 1, 1994): 441–46. http://dx.doi.org/10.1139/y94-064.
Full textAbstract:
When carbon tetrachloride (CCl4) was administered to rats, a localized region of hepatic edema could be detected within 1 h by in vivo proton magnetic resonance imaging. However, if rats were pretreated with gadolinium chloride (GdCl3), an inhibitor of Kupffer cell function, the CCl4-induced edema was greatly decreased. Methyl palmitate, another Kupffer cell inhibitor, also decreased the degree of edema caused by the administration of CCl4. Electron micrographs of samples that were taken from regions of the liver where the edema was localized indicated formation of vacuoles and lipid droplets in parenchymal cells and enlargement of Kupffer cells, which exhibited numerous phagosomes and extensive pseudopod formation. These electron micrograph changes were also attenuated by pretreatment of the rats with GdCl3 and methyl palmitate. In vivo spin trapping and electron paramagnetic resonance experiments indicated that GdCl3 did not affect the metabolism of CCl4 to the trichloromethyl radical. The data in this report suggest that localized hepatic edema which occurs soon after administration of CCl4 involves activation of Kupffer cells, and that trichloromethyl radical production may be a separate but related process occurring in parenchymal cells. These observations support reports from other laboratories that Kupffer cells may be involved in CCl4-induced hepatotoxicity.Key words: carbon tetrachloride, hepatotoxicity, magnetic resonance imaging, gadolinium chloride, Kupffer cells.
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Kohara, Sho, and Kazushige Ogawa. "Eph/Ephrin Promotes the Adhesion of Liver Tissue-Resident Macrophages to a Mimicked Surface of Liver Sinusoidal Endothelial Cells." Biomedicines 10, no. 12 (December 12, 2022): 3234. http://dx.doi.org/10.3390/biomedicines10123234.
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Kupffer cells are maintained via self-renewal in specific microenvironmental niches, primarily the liver sinusoidal endothelial cells (LSECs). In this study, we propagated tissue-resident macrophages (Mø) from mouse liver using mixed culture with hepatic fibroblastic cells. Propagated liver Mø express Id3, Lxra and Spic transcription factors, which are required for Kupffer cell characterization. Thus, Kupffer cell properties are likely to be maintained in liver Mø propagated using mixed culture with fibroblastic cells. We revealed (i) gene expression of certain Eph receptors and ephrin ligands including EphA2, ephrin-A1, EphB4, and ephrin-B1 in propagated liver Mø and primary LSECs, (ii) immunohistochemical localization of these Eph/ephrin member molecules indicating common expression in Kupffer cells and LSECs, and (iii) surface expression of several integrin α and β subunits, including α4β1, αLβ2, αMβ2, and αXβ2 integrin in propagated liver Mø and that of the corresponding ligands ICAM-1 and VCAM-1 in primary LSECs. Moreover, EphA/ephrin-A and EphB/ephrin-B interactions promoted liver Mø adhesion to the ICAM-1-adsorbed surface, which mimicked that of LSECs and may be implicated in the residence of Kupffer cells in the liver sinusoid. Further studies on regulating the residence and regeneration of Kupffer cells in related hepatic disorders are required to validate our findings.
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Asmoro, Aswoco Andyk, Wiwi Jaya, Andri Nur Wahyudi, and Ristiawan Muji Laksono. "The effect of ketamine on Kupffer cell count in Wistar rat (Rattus norvegicus) model of sepsis." Anaesthesia, Pain & Intensive Care 26, no. 4 (August 15, 2022): 445–49. http://dx.doi.org/10.35975/apic.v26i4.1946.
Full textAbstract:
Background: Sepsis is a serious health problem and is associated with life-threatening complications, such as liver dysfunction, renal failure as well as cardiorespiratory disease. Kupffer cells are immune cells that contribute to the pathogenesis of liver dysfunction. This study aims to determine the effect of ketamine on the number of Kupffer cells in experimental animal models of sepsis.
Methodology: This experimental study used fecal-induced peritonitis (FIP) to create a sepsis model in rats (Rattus norvegicus). Thirty rats were divided into six equal groups, namely the negative control group, which was not treated with FIP (Group K−), the positive control group or the sepsis model with FIP treatment (Group K+), and the treatment group; the sepsis model rats (FIP treatment) given 5 mg of ketamine/kg intraperitoneally once at 0 h (Group A), at 3 h (Group B), 5 h (Group C) after induction of sepsis with FIP, and every 2 h after induction of sepsis with FIP for four hours (Group D). Kupffer cells were counted six hours after FIP induction using a hematology analyzer. Statistical test was carried out using the One-Way ANOVA test using SPSS 18.0 software.
Results: The number of Kupffer cells in sepsis groups (K+) was significantly higher (22.60 cell/ml) than in the negative control group (K-) (12.68 cell/ml) (P= 0.01). The administration of ketamine in the sepsis model group significantly decreased the number of Kupffer cells close to normal. The number of Kupffer cells was 12.56 cells/ml in Group A, 12.92 cells/ml in Group B, 9.75 cells/ml in Group C, and 8.50 cells/ml in Group D.
Conclusion: The administration of ketamine decreased the number of Kupffer cells in the rat model of sepsis induced by FIP to close to the normal group.
Abbreviations: APP - acute-phase protein; FIP - fecal induced peritonitis; ICU - Intensive Care Unit; IL – interleukin; KCs - Kupffer cells; ROS - reactive oxygen species; NO - nitric oxide; SIRS - systemic inflammatory response syndrome; TNF-α - tumor necrosis factor-alpha.
Keywords: Immunomodulator; Ketamine; Kupffer cell; Sepsis
Citation: Asmoro AA, Jaya W, Wahyudi AN, Laksono RM. The effect of ketamine on Kupffer cell count in Wistar rat (Rattus norvegicus) model of sepsis. Anaesth. pain intensive care 2022;26(4): 445-449.
DOI: 10.35975/apic.v26i4.1946
Received: April 20, 2022; Reviewed: July 13, 2022; Accepted: July 13, 2022
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Sichel, Giovanni, Marina Scalia, and Concetta Corsaro. "Amphibia Kupffer cells." Microscopy Research and Technique 57, no. 6 (June 15, 2002): 477–90. http://dx.doi.org/10.1002/jemt.10101.
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Qu, W., Z. Zhong, M. Goto, and R. G. Thurman. "Kupffer cell prostaglandin E2 stimulates parenchymal cell O2 consumption: alcohol and cell-cell communication." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 4 (April 1, 1996): G574—G580. http://dx.doi.org/10.1152/ajpgi.1996.270.4.g574.
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Several studies have demonstrated that ethanol can increase hepatic O2 uptake (e.g., produce a hypermetabolic state); however, a complete explanation of this important phenomenon remains unclear. Here, the effect of conditioned media from Kupffer cells isolated from rats chronically exposed to ethanol on O2 consumption of normal parenchymal cells was studied to evaluate the possibility that cell-cell communication participates in the mechanism of the hepatic hypermetabolic state. Kupffer cells were isolated from rats fed either a liquid control diet or a diet containing ethanol. Kupffer cells were cultured for 4 h, and conditioned media were incubated with parenchymal cells isolated from untreated rats in a closed chamber with an O2 electrode. O2 consumption of parenchymal cells incubated in fresh media or conditioned media from Kupffer cells from untreated rats was approximately 30 microliters.h-1. 10(6) cells-1; however, values were increased by > 30% by conditioned media from Kupffer cells isolated from rats treated with ethanol. Indomethacin, nisoldipine, and boiling the conditioned media blocked this stimulation, suggesting the involvement of eicosanoids. Indeed, prostaglandin E2 (PGE2) added directly to parenchymal cells increased O2 consumption in a dose-dependent manner by nearly 60%. Furthermore, PGE2 levels in conditioned media from Kupffer cells isolated from ethanol-treated rats were elevated about twofold. The addition of endotoxin to cultured cells caused a similar phenomenon. Taken together, these data support the hypothesis that Kupffer cells are activated by ethanol treatment to release mediators such a PGE2, which stimulate O2 consumption in parenchymal cells, possibly by mechanisms involving bacterial endotoxin.
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Schouten, D., M. Kleinherenbrink-Stins, A. Brouwer, D. L. Knook, and T. J. C. Van Berkel. "Interaction in vivo and in vitro of apolipoprotein E-free high-density lipoprotein with parenchymal, endothelial and Kupffer cells from rat liver." Biochemical Journal 256, no. 2 (December 1, 1988): 615–21. http://dx.doi.org/10.1042/bj2560615.
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The interaction of apolipoprotein (apo) E-free high-density lipoprotein (HDL) with parenchymal, endothelial and Kupffer cells from liver was characterized. At 10 min after injection of radiolabelled HDL into rats, 1.0 +/- 0.1% of the radioactivity was associated with the liver. Subfractionation of the liver into parenchymal, endothelial and Kupffer cells, by a low-temperature cell-isolation procedure, indicated that 77.8 +/- 2.4% of the total liver-associated radioactivity was recovered with parenchymal cells, 10.8 +/- 0.8% with endothelial cells and 11.3 +/- 1.7% with Kupffer cells. It can be concluded that inside the liver a substantial part of HDL becomes associated with endothelial and Kupffer cells in addition to parenchymal cells. With freshly isolated parenchymal, endothelial and Kupffer cells the binding properties for apo E-free HDL were determined. For parenchymal, endothelial and Kupffer cells, evidence was obtained for a saturable, specific, high-affinity binding site with Kd and Bmax. values respectively in the ranges 10-20 micrograms of HDL/ml and 25-50 ng of HDL/mg of cell protein. In all three cell types nitrosylated HDL and low-density lipoproteins did not compete for the binding of native HDL, indicating that lipids and apo B are not involved in specific apo E-free HDL binding. Very-low-density lipoproteins (VLDL), however, did compete for HDL binding. The competition of VLDL with apo E-free HDL could not be explained by label exchange or by transfer of radioactive lipids or apolipoproteins between HDL and VLDL, and it is therefore suggested that competition is exerted by the presence of apo Cs in VLDL. The results presented here provide evidence for a high-affinity recognition site for HDL on parenchymal, liver endothelial and Kupffer cells, with identical recognition properties on the three cell types. HDL is expected to deliver cholesterol from peripheral cells, including endothelial and Kupffer cells, to the liver hepatocytes, where cholesterol can be converted into bile acids and thereby irreversibly removed from the circulation. The observed identical recognition properties of the HDL high-affinity site on liver parenchymal, endothelial and Kupffer cells suggest that one receptor may mediate both cholesterol efflux and cholesterol influx, and that the regulation of this bidirectional cholesterol (ester) flux lies beyond the initial binding of HDL to the receptor.
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Brock, Robert W., Robert G. Nie, Kenneth A. Harris, and Richard F. Potter. "Kupffer cell-initiated remote hepatic injury following bilateral hindlimb ischemia is complement dependent." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 2 (February 1, 2001): G279—G284. http://dx.doi.org/10.1152/ajpgi.2001.280.2.g279.
Full textAbstract:
Intravital fluorescence microscopy was applied to the livers of male Wistar rats to test the hypothesis that complement mobilization stimulates Kupffer cells and subsequently initiates hepatic injury after hindlimb ischemia/reperfusion (I/R). Following 3 h of limb reperfusion, hepatocellular viability (serum levels of alanine transaminase and cell death via propidium iodide labeling) decreased significantly from levels in sham-operated animals. Inhibition of complement mobilization with soluble complement receptor type 1 (20 mg/kg body wt) and interruption of Kupffer cell function with GdCl3 (1 mg/100g body wt) resulted in significant hepatocellular protection. Although the effects of hindlimb I/R on hepatic microvascular perfusion were manifest as increased heterogeneity, both complement inhibition and suppression of Kupffer cell function resulted in marked improvements. No additional hepatocellular protection and microvascular improvements were provided by combining the interventions. Furthermore, inhibition of complement mobilization significantly depressed Kupffer cell phagocytosis by 42% following limb reperfusion. These results suggest that the stimulation of Kupffer cells via complement mobilization is necessary but is not the only factor contributing to the early pathogenesis of hepatic injury following hindlimb I/R.
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Maher, J. J. "Rat hepatocytes and Kupffer cells interact to produce interleukin-8 (CINC) in the setting of ethanol." American Journal of Physiology-Gastrointestinal and Liver Physiology 269, no. 4 (October 1, 1995): G518—G523. http://dx.doi.org/10.1152/ajpgi.1995.269.4.g518.
Full textAbstract:
Interleukin-8 is a neutrophil chemoattractant that has been implicated in the pathogenesis of alcoholic hepatitis. The mechanism of ethanol-induced interleukin-8 production in liver is uncertain, although hepatocytes and Kupffer cells have both been proposed as sources of the chemokine. In this study we investigated whether short-term ethanol exposure stimulates production of rat interleukin-8 [cytokine-induced neutrophil chemoattractant (CINC)] by normal rat hepatocytes and Kupffer cells in primary culture. Initial experiments verified that hepatocytes and Kupffer cells produce CINC in response to cytokines or lipopolysaccharide. Ethanol, by contrast, failed to stimulate CINC secretion by either cell type even at concentrations as high as 100 mM. Although ethanol had no direct effect on liver cell CINC production, conditioned medium from ethanol-treated hepatocytes induced a threefold rise in CINC production by Kupffer cells. The increase was abrogated when hepatocytes were treated with ethanol and the metabolic inhibitor 4-methylpyrazole. The results suggest that the mechanism of ethanol-induced CINC production is indirect, involving ethanol oxidation and communication between hepatocytes and Kupffer cells.
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Klein, Ingo, Judith C. Cornejo, Noelle K. Polakos, Beena John, Sherry A. Wuensch, David J. Topham, Robert H. Pierce, and Ian Nicholas Crispe. "Kupffer cell heterogeneity: functional properties of bone marrow–derived and sessile hepatic macrophages." Blood 110, no. 12 (December 1, 2007): 4077–85. http://dx.doi.org/10.1182/blood-2007-02-073841.
Full textAbstract:
Abstract Kupffer cells form a large intravascular macrophage bed in the liver sinusoids. The differentiation history and diversity of Kupffer cells is disputed; some studies argue that they are derived from blood monocytes, whereas others support a local origin from intrahepatic precursor cells. In the present study, we used both flow cytometry and immunohistochemistry to distinguish 2 subsets of Kupffer cells that were revealed in the context both of bone marrow transplantation and of orthotopic liver transplantation. One subset was radiosensitive and rapidly replaced from hematogenous precursors, whereas the other was relatively radioresistant and long-lived. Both were phagocytic but only the former population was recruited into inflammatory foci in response to CD8+ T-cell activation. We propose the name “sessile” for the radioresistant Kupffer cells that do not participate in immunoinflammatory reactions. However, we found no evidence that these sessile Kupffer cells arise from immature intrahepatic precursors. Our conclusions resolve a long-standing controversy and explain how different experimental approaches may reveal one or both of these subsets.
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Jaeschke, H., and A. Farhood. "Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver." American Journal of Physiology-Gastrointestinal and Liver Physiology 260, no. 3 (March 1, 1991): G355—G362. http://dx.doi.org/10.1152/ajpgi.1991.260.3.g355.
Full textAbstract:
The hypothesis that Kupffer cells and infiltrating neutrophils generate reactive oxygen in the hepatic sinusoids and may contribute to ischemia-reperfusion injury in the liver was investigated in a model of partial no-flow ischemia and reperfusion in male Fischer rats in vivo. During the reperfusion period of 60 min, plasma concentrations of glutathione disulfide (GSSG; index of oxidant stress) increased from 1.62 +/- 0.20 microM glutathione (GSH) equivalents to maximal values of 11.82 +/- 1.45 (45 min ischemia), 24.19 +/- 2.35 (60 min ischemia), and 70.20 +/- 7.8 (120 min ischemia). The basal tissue GSSG content in the postischemic lobes (0.19 +/- 0.02 nmol GSH eq/mg protein) increased by 50-100%. Although the number of neutrophils in liver and lung increased by 3- to 10-fold during reperfusion, there was no positive correlation between the number of neutrophils and the GSSG concentrations measured in plasma or tissue. However, activation of Kupffer cells with high doses of retinol or with Propionibacterium acnes significantly enhanced plasma GSSG levels, while inactivation of Kupffer cells with methyl palmitate or gadolinium chloride significantly attenuated the increase of plasma GSSG. Inactivation of Kupffer cells protected the liver significantly against ischemia-reperfusion injury. It is concluded that Kupffer cells are the predominant source of reactive oxygen formed during the initial reperfusion period and that Kupffer cell activity (including reactive oxygen formation) contributes to reperfusion injury in the liver in vivo.
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Lindert, K. A., J. C. Caldwell-Kenkel, S. Nukina, J. J. Lemasters, and R. G. Thurman. "Activation of Kupffer cells on reperfusion following hypoxia: particle phagocytosis in a low-flow, reflow model." American Journal of Physiology-Gastrointestinal and Liver Physiology 262, no. 2 (February 1, 1992): G345—G350. http://dx.doi.org/10.1152/ajpgi.1992.262.2.g345.
Full textAbstract:
Hypoxia is produced selectively in pericentral regions of the liver lobule with a low-flow, reflow perfusion model in which the flow rate is reduced to approximately one-third to one-fourth of normal. This model was used to monitor carbon particle phagocytosis by Kupffer cells during hypoxia and reoxygenation. At normal flow rates, oxygen uptake was 131 mumol.g-1.h-1, pressure was 7.5 cmH2O, and carbon uptake was 150 mg.g-1.h-1. During the low-flow period, oxygen uptake, pressure, and carbon uptake decreased to values of 54 mumol.g-1.h-1, 6.4 cmH2O and 83 mg.g-1.h-1, respectively. Upon reflow, oxygen uptake and pressure increased to 141 mumol.g-1.h-1 and 10.3 cmH2O, respectively. In addition, carbon uptake was elevated approximately threefold to 234 mg.g-1.h-1, indicating activation of Kupffer cells. This activation was prevented by pretreatment with methyl palmitate, a known inhibitor of Kupffer cells. Histological examination revealed significantly more Kupffer cells laden with carbon particles in untreated livers after reflow than in livers from methyl palmitate-treated or untreated rats. Electron microscopic analysis of livers at reflow revealed Kupffer cells with numerous pseudopodia and lamellapodia, reflecting an activated state. These changes were absent in controls or in livers perfused under low-flow conditions. This study demonstrates that Kupffer cells are activated on reoxygenation after hypoxia.
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Bijsterbosch, M. K., and T. J. C. Van Berkel. "Uptake of lactosylated low-density lipoprotein by galactose-specific receptors in rat liver." Biochemical Journal 270, no. 1 (August 15, 1990): 233–39. http://dx.doi.org/10.1042/bj2700233.
Full textAbstract:
The liver contains two types of galactose receptors, specific for Kupffer and parenchymal cells respectively. These receptors are only expressed in the liver, and therefore are attractive targets for the specific delivery of drugs. We provided low-density lipoprotein (LDL), a particle with a diameter of 23 nm in which a variety of drugs can be incorporated, with terminal galactose residues by lactosylation. Radioiodinated LDL, lactosylated to various extents (60-400 mol of lactose/ mol of LDL), was injected into rats. The plasma clearance and hepatic uptake of radioactivity were correlated with the extent of lactosylation. Highly lactosylated LDL (greater than 300 lactose/LDL) is completely cleared from the blood by liver within 10 min. Pre-injection with N-acetylgalactosamine blocks liver uptake, which indicates that the hepatic recognition sites are galactose-specific. The hepatic uptake occurs mainly by parenchymal and Kupffer cells. At a low degree of lactosylation, approx. 60 lactose/LDL, the specific uptake (ng/mg of cell protein) is 28 times higher in Kupffer cells than in parenchymal cells. However, because of their much larger mass, parenchymal cells are the main site of uptake. At high degrees of lactosylation (greater than 300 lactose/LDL), the specific uptake in Kupffer cells is 70-95 times that in parenchymal cells. Under these conditions, Kupffer cells are, despite their much smaller mass, the main site of uptake. Thus not only the size but also the surface density of galactose on lactosylated LDL is important for the balance of uptake between Kupffer and parenchymal cells. This knowledge should allow us to design particulate galactose-bearing carriers for the rapid transport of various drugs to either parenchymal cells or Kupffer cells.
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van Berkel, T. J. C., C. J. Dekker, J. K. Kruijt, and H. G. van Eijk. "The interaction in vivo of transferrin and asialotransferrin with liver cells." Biochemical Journal 243, no. 3 (May 1, 1987): 715–22. http://dx.doi.org/10.1042/bj2430715.
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Rat transferrin or asialotransferrin doubly radiolabelled with 59Fe and 125I was injected into rats. A determination of extrahepatic and hepatic uptake indicated that asialotransferrin delivers a higher fraction of the injected 59Fe to the liver than does transferrin. In order to determine in vivo the intrahepatic recognition sites for transferrin and asialotransferrin, the liver was subfractionated into parenchymal, endothelial and Kupffer cells by a low-temperature cell isolation procedure. High-affinity recognition of transferrin (competed for by an excess of unlabelled transferrin) is exerted by parenchymal cells as well as endothelial and Kupffer cells with a 10-fold higher association (expressed per mg of cell protein) to the latter cell types. In all three cell types iron delivery occurs, as concluded from the increase in cellular 59Fe/125I ratio at prolonged circulation times of transferrin. It can be calculated that parenchymal cells are responsible for 50-60% of the interaction of transferrin with the liver, 20-30% is associated with endothelial cells and about 20% with Kupffer cells. For asialotransferrin a higher fraction of the injected dose becomes associated with parenchymal cells as well as with endothelial and Kupffer cells. Competition experiments in vivo with various sugars indicated that the increased interaction of asialotransferrin with parenchymal cells is specifically inhibited by N-acetylgalactosamine whereas mannan specifically inhibits the increased interaction of asialotransferrin with endothelial and Kupffer cells. Recognition of asialotransferrin by galactose receptors from parenchymal cells or mannose receptors from endothelial and Kupffer cells is coupled to active 59Fe delivery to the cells. It is concluded that, as well as parenchymal cells, liver endothelial and Kupffer cells are also quantitatively important intrahepatic sites for transferrin and asialotransferrin metabolism, an interaction exerted by multiple recognition sites on the various cell types.
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Brouwer, A., S. G. Parker, H. F. J. Hendriks, L. Gibbons, and M. A. Horan. "Production of Eicosanoids and Cytokines by Kupffer Cells from Young and Old Rats Stimulated by Endotoxin." Clinical Science 88, no. 2 (February 1, 1995): 211–17. http://dx.doi.org/10.1042/cs0880211.
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1. The clinicopathological features of endotoxaemia have been ascribed to cytotoxic mediators such as tumour necrosis factor, interleukins and eicosanoids. Macrophages, particularly Kupffer cells, are an important source of these mediators. Mortality from endotoxaemia is highly age related. 2. These studies focus on the role of hepatic Kupffer cells in the increased sensitivity of old rats to bacterial endotoxins. Possible age-related changes in the production of eicosanoids and induction of gene expression and secretion of interleukin 1, tumour necrosis factor and interleukin 6 were investigated in Kupffer cells derived from both young and old animals. 3. Basal production of biological response modifiers was low in cells of both young and old rats. Lipopolysaccharide stimulated production of the same types of monokines as described for other types of macrophages, although the pattern was specific for Kupffer cells. 4. Eicosanoids, predominantly prostaglandin D2 and prostaglandin F2α, were produced mainly during the first hour after exposure to lipopolysaccharide. Endotoxin stimulated synthesis of mRNAs of interleukin 1, interleukin 6 and tumour necrosis factor α resulting in increased secretion of these cytokines into the medium. 5. Kupffer cells from both young and aged animals appear to be exquisitely sensitive to endotoxin in respect of expression of mRNA for both interleukin 1α and interleukin 1β and less sensitive with respect to interleukin 6 and tumour necrosis factor α gene expression. At relatively high lipopolysaccharide concentrations interleukin 6 was secreted in particularly large amounts. 6. The effects of ageing on any of these responses of Kupffer cells were minimal. 7. It seems unlikely that age-related changes in the synthesis and secretion of eicosanoids and cytokines by Kupffer cells are an important factor in the increased susceptibility of old rats to LPS.
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Huynh, T., C. C. Baker, L. W. Bracey, and J. J. Lemasters. "Adaptive Kupffer cell alterations after femur fracture trauma in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 272, no. 6 (June 1, 1997): G1457—G1462. http://dx.doi.org/10.1152/ajpgi.1997.272.6.g1457.
Full textAbstract:
Because Kupffer cells constitute the largest fixed macrophage population and reside at a strategic position in hepatic sinusoids, interacting with hepatocytes, circulating cells, and mediators from the gut, they may be important in the inflammatory response after injury. This study examined the effect of remote tissue injury on Kupffer cell function. Femurs of Sprague-Dawley rats were fractured under anesthesia. Subsequently, their livers were perfused for measurement of oxygen consumption and the isolation and culture of Kupffer cells. At 2 and 48 h after femur fracture, hepatic oxygen consumption increased 17 and 19%, respectively. Gadolinium chloride pretreatment to ablate Kupffer cells blocked this increase of hepatic oxygen consumption after femur fracture but had no effect in sham-operated animals. In Kupffer cells isolated and cultured 2 h after femur fracture, superoxide formation stimulated by phorbol ester increased eightfold, phagocytosis increased fourfold, and lipopolysaccharide (LPS)-stimulated prostaglandin E2 increased sixfold in comparison to sham-operated controls. In contrast, LPS-stimulated tumor necrosis factor-alpha and nitric oxide production decreased 50 and 60%, respectively. These data show that peripheral trauma rapidly induces changes in hepatic macrophages characterized by adaptation to a more antimicrobial and less proinflammatory phenotype.
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Ikejima, K., W. Qu, R. F. Stachlewitz, and R. G. Thurman. "Kupffer cells contain a glycine-gated chloride channel." American Journal of Physiology-Gastrointestinal and Liver Physiology 272, no. 6 (June 1, 1997): G1581—G1586. http://dx.doi.org/10.1152/ajpgi.1997.272.6.g1581.
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Here the effect of glycine on intracellular Ca2+ concentration ([Ca2+]i) in cultured Kupffer cells stimulated with lipopolysaccharide (LPS) was investigated to assess the possibility that they contain a glycine-gated chloride channel. LPS (10 micrograms/ml) increased [Ca2+]i rapidly, with peak values reaching 307 +/- 29 nM. Glycine (1 mM) prevented this increase nearly completely. Low concentrations of strychnine (1 microM), a glycine receptor antagonist, reversed the inhibitory effect of glycine completely; however, high concentrations of strychnine (1 mM) mimicked glycine. The effects of glycine and high-dose strychnine were prevented when cells were incubated in chloride-free buffer. Furthermore, potassium (25 mM) and LPS depolarized the Kupffer cell plasma membrane, whereas glycine caused hyperpolarization and prevented depolarization due to potassium and LPS. Moreover, tumor necrosis factor-alpha (TNF-alpha) production in cultured Kupffer cells due to LPS was decreased significantly by glycine. Therefore, it is concluded that Kupffer cells contain a glycine-gated chloride channel similar to that described previously in the central nervous system. Prevention of increases in [Ca2+]i due to LPS by activation of chloride influx reduced synthesis and release of toxic mediators by Kupffer cells.
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Watanabe, J., K. Kanai, and S. Kanamura. "Glucagon receptors in endothelial and Kupffer cells of mouse liver." Journal of Histochemistry & Cytochemistry 36, no. 9 (September 1988): 1081–89. http://dx.doi.org/10.1177/36.9.2841370.
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To determine whether hepatic sinusoidal cells contain glucagon receptors and, if so, to study the significance of the receptors in the cells, binding of [125I]-glucagon to nonparenchymal cells (mainly endothelial cells and Kupffer cells) isolated from mouse liver was examined by quantitative autoradiography and biochemical methods. Furthermore, the pathway of intracellular transport of colloidal gold-labeled glucagon (AuG) was examined in vivo. Autoradiographic and biochemical results demonstrated many glucagon receptors in both endothelial cells and Kupffer cells, and more receptors being present in endothelial cells than in Kupffer cells. In vivo, endothelial cells internalized AuG particles into coated vesicles via coated pits and transported the particles to endosomes, lysosomes, and abluminal plasma membrane. Therefore, receptor-mediated transcytosis of AuG occurs in endothelial cells. The number of particles present on the abluminal plasma membrane was constant if the amount of injected AuG increased. Therefore, the magnitude of receptor-mediated transcytosis of AuG appears to be regulated by endothelial cells. Kupffer cells internalized the ligand into cytoplasmic tubular structures via plasma membrane invaginations and transported the ligand exclusively to endosomes and lysosomes, suggesting that the ligand is degraded by Kupffer cells.
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Ziamko, V., V. Okulich, and A. Dzyadzko. "Role of Kupfer cells in development of the immune response in liver transplantation cytokines in viral infection." Immunopathology, Allergology, Infectology 2021, no. 2 (April 1, 2021): 6–12. http://dx.doi.org/10.14427/jipai.2021.2.6.
Full textAbstract:
Kupffer cells are a large collection of resident tissue macrophages derived from monocytes and producing pro- and anti-inflammatory cytokines, proteases and oxygen radicals that promote the induction and stimulation of immunity to various pathogens, but at the same time can lead to liver damage. This review provides a better idea of the mechanism of graft rejection due to hyperactivation of Kupffer cells. Possible methods of inhibition of Kupffer cells without the subsequent development of hepatotoxicity are considered that may have a potential to prevent a hyperimmune response and organ rejection.
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Su, Grace L. "Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 2 (August 1, 2002): G256—G265. http://dx.doi.org/10.1152/ajpgi.00550.2001.
Full textAbstract:
Endogenous gut-derived bacterial lipopolysaccharides have been implicated as important cofactors in the pathogenesis of liver injury. However, the molecular mechanisms by which lipopolysaccharides exert their effect are not entirely clear. Recent studies have pointed to proinflammatory cytokines such as tumor necrosis factor-α as mediators of hepatocyte injury. Within the liver, Kupffer cells are major sources of proinflammatory cytokines that are produced in response to lipopolysaccharides. This review will focus on three important molecular components of the pathway by which lipopolysaccharides activate Kupffer cells: CD14, Toll-like receptor 4, and lipopolysaccharide binding protein. Within the liver, lipopolysaccharides bind to lipopolysaccharide binding protein, which then facilitates its transfer to membrane CD14 on the surface of Kupffer cells. Signaling of lipopolysaccharide through CD14 is mediated by the downstream receptor Toll-like receptor 4 and results in activation of Kupffer cells. The role played by these molecules in liver injury will be examined.