Phagocytic Activity Of Kupffer Cells Research Articles

Evaluation of oxidized beta-carotene on sow and piglet immune systems, sow reproductive performance, and piglet growth.

This study aimed to determine if supplementation of oxidized-beta carotene (OxC-Beta) improved sow reproductive performance, litter growth performance, vitamin A status, and ability to alter immune cells abundance in sows and piglets, subsequent litter performance, and nursery growth performance. At approximately d 60 of gestation and through the lactation period, 194 sows (blocked by parity) were assigned to a common gestation diet or the common diet supplemented with 80ppm oxidized beta-carotene (OxC-Beta, Aviagen, Ottawa, ON, Canada). A subset of sows (n = 54 per treatment) were sampled for blood and body weight recorded at the beginning of the study, farrowing, and weaning. A blood sample was taken from a subset of piglets at birth and weaning, and all piglet weights were recorded. Blood was analyzed for vitamin A as retinol concentrations and immunoglobulin G (IgG) and immunoglobulin M (IgG) levels were assessed from the sow's blood. Twelve pigs (n = 6 per treatment) were euthanized at birth and weaning. The livers were collected and analyzed for the Kupffer cell phagocytic activity through flow cytometry. Whole blood was analyzed via flow cytometry for cluster of differentiation (CD335, CD8, and CD4). Colostrum during farrowing and milk at weaning were analyzed for IgG and IgA concentrations. Data were analyzed via SAS 9.4 using MIXED and frequency procedures where appropriate. No differences (P > 0.05) between dietary treatments were observed in sow reproductive performance, feed intake, wean to estrus interval, or piglet growth performance. No differences (P > 0.05) were observed in the plasma or liver for vitamin A. No differences (P > 0.05) were observed in the composition of the colostrum or milk. No immunological differences (P > 0.05) were observed in the piglets' liver and blood or sow antibodies in colostrum and milk. The supplementation of OxC-Beta did (P < 0.05) decrease IgM and tended (P < 0.10) to decrease IgG in sow plasma. No differences (P > 0.05) were observed in the reproductive performance of subsequent litter information from the sows. Gilt litter weaning weight and feed intake were reduced (P < 0.05) compared to sow performance. In conclusion, the supplementation of OxC-Beta at 80ppm from d 60 of gestation through lactation does not affect the reproductive performance of sows, litter growth performance, vitamin A status, piglet immune status, and antibodies or composition in colostrum and milk.

Anti-CD47 Antibody Enhances the Efficacy of Chemotherapy in Patients with Gastric Cancer Liver Metastasis.

Patients with gastric cancer liver metastasis (GCLM) are often treated with palliative care, and they show a poor prognosis. In gastric cancer, high CD47 expression has been shown to indicate a poor prognosis. CD47, expressed on the cell surface, prevents the cells from being phagocytosed by macrophages. Anti-CD47 antibodies have been shown to be effective in the treatment of metastatic leiomyosarcoma. Nonetheless, the role of CD47 in GCLM has not yet been elucidated. Here, we showed that CD47 expression in GCLM tissues was higher than that in situ. Moreover, we demonstrated that high CD47 expression correlated with an adverse prognosis. Accordingly, we investigated the role of CD47 in the development of GCLM in mouse liver. Knockdown of CD47 inhibited GCLM development. Furthermore, in vitro engulfment assays showed that decreased CD47 expression led to an increased phagocytic activity of Kupffer cells (KCs). Using enzyme-linked immunosorbent assay, we determined that CD47 knockdown promoted cytokine secretion by macrophages. Furthermore, we found that tumor-derived exosomes decreased KC-mediated phagocytosis of gastric cancer cells. Finally, in a heterotopic xenograft model, the administration of anti-CD47 antibodies inhibited tumor growth. In addition, as 5-fluorouracil (5-Fu)-based chemotherapy is the cornerstone in GCLM treatment, we administered a combination of anti-CD47 antibodies and 5-Fu, which acted synergistically to suppress the tumor. Overall, we demonstrated that tumor-derived exosomes are involved in GCLM progression, targeting CD47 inhibits gastric cancer tumorigenesis, and a combination of anti-CD47 antibodies and 5-Fu shows potential for treating GCLM.

Antiplasmodial activity of chalcone derivatives compound through phagocytosis of kupffer cells in experimental malaria hosts

Introduction: Malaria is still one of the major health problems, specifically due to drug resistance in Plasmodium, which encourages extensive research to find effective alternatives. One of the new antimalarial compounds is chalcone-derivative compound (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl)prop-2-en-1-one. However, its potency is still needed to be evaluated. Therefore, this study aimed to determine the efficacy and identify the pharmacological mechanism of this chalcone-derivative. Methods: An experiment using post-test only with control group design was conducted from May 2016 to July 2017 in the laboratory of Parasitology and Clinical Pathology Faculty of Medicine, Universitas Gadjah Mada. Swiss mice were used and infected with Plasmodium before being divided into nine groups with different concentrations of (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl)prop-2-en-1-one. Histological examination was conducted to count the number of Kupffer cells and the proportion of Kupffer cells that had phagocytosed the Plasmodium. Results: Both doxycycline and (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl)prop-2-en-1-one  decreased the parasitemia in the tested mice with higher efficacy was observed in the doxycycline group. Likewise, both compounds also increase the number of Kupffer cells which become phagocytes of erythrocytes containing Plasmodium was higher in the treatment group than in the control group (p 0.000 &lt;0.05). Substance (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl) prop-2-en-1-one may act as an antimalarial by phagocytes of erythrocytes containing Plasmodium. Conclusion In conclusion, the (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl)prop-2-en-1-one exhibited potent antimalarial activity via the phagocytic activity of Kupffer cells. This compound may be developed into a new antimalarial drug.

Enhanced Opsonization-Independent Phagocytosis and High Response Ability to Opsonized Antigen–Antibody Complexes: A New Role of Kupffer Cells in the Accelerated Blood Clearance Phenomenon upon Repeated Injection of PEGylated Emulsions

The accelerated blood clearance (ABC) phenomenon is an immune response against the first injection of PEGylated colloidal drug delivery systems (CDDSs), which causes the accelerated clearance of the second dose. The enhanced complement-mediated phagocytic activity of Kupffer cells is responsible for accelerated second-dose clearance. Nevertheless, few studies have focused on the role of Kupffer cells in the induction phase of the ABC phenomenon. In this study, the intrinsic phagocytic activity of Kupffer cells was significantly enhanced at 6 days after the initial injected PEGylated emulsions (PEs) using the carbon clearance test and single-pass liver perfusion experiment. Furthermore, PE could stimulate Kupffer cells activation, leading to enhanced cell viability of Kupffer cells and opsonization-independent cellular uptake. It was also found that the response ability of Kupffer cells to the antigen-antibody complexes was augmented by the first injection of PE. Conclusively, we proposed that, besides anti-PEG IgM and complement activation-mediated hepatic uptake, enhanced opsonization-independent phagocytosis of Kupffer cells and the high response ability to opsonized antigen-antibody complexes contribute to the accelerated clearance of the second administration. The results indicated that Kupffer cells play an indispensable role in the ABC phenomenon and provided novel insights into the current view on the mechanism of the ABC effect.

SUN-LB316: Influences of Aging on the Phagocytic Activity of Kupffer Cells in Mice

SUN-LB316: Influences of Aging on the Phagocytic Activity of Kupffer Cells in Mice

Image Monitoring of the Impaired Phagocytic Activity of Kupffer Cells and Liver Oxygen Saturation in a Mouse Cholangitis Model Using Contrast-Enhanced Ultrasound Imaging and Photoacoustic Imaging

Bile duct ligation (BDL) can cause cholangitis, which is known to induce impaired Kupffer cell (KC) function and increased oxygen consumption in a mouse model. It is important to monitor changes in KC function and tissue oxygen saturation, both of which are critical factors in the progression of cholangitis. The purpose of this study is to investigate the impaired phagocytic activity of KC and liver oxygen saturation (sO2) in a mouse cholangitis model using contrast-enhanced ultrasound imaging (CEUS) and photoacoustic imaging (PAI). A mouse cholangitis model was created by ligation of the common bile duct (CBDL, n = 20), and the left intrahepatic bile duct (BDL-L, n = 19), both of which were compared with the non-ligation groups—right lobe measurement group after left intrahepatic bile duct ligation (BDL-R, n = 19) and the control group (n = 14). The echogenicity and sO2 were measured by CEUS and PAI and the KC fraction was assessed at 1, 2 and 4 wk after ligation. We found a significantly lower echogenicity of the Kupffer phase in the CBDL and BDL-L groups compared with that in the control and BDL-R groups at 2 wk (p < .01). The CBDL and BDL-L groups showed a lower echogenicity than that of the BDL-R group at 4 wk (p < .01). We found a significantly lower sO2 of the CBDL and BDL-L groups compared with that of the control and BDL-R groups at 4 wk (p < .01). The CBDL and BDL-L groups showed a higher KC fraction than that of the BDL-R and control groups at each time point (p < .01). In conclusion, our study suggests that the Sonazoid CEUS and PAI could be a useful tool for monitoring impaired KC phagocytic activity and the liver hypoxic state.

The activation of Epimedium polysaccharide-propolis flavone liposome on Kupffer cells

Epimedium polysaccharide-propolis flavone liposome (EPL), a potent immunological pharmaceutical preparation, was investigated for the immunomodulatory activity on Kupffer cells (KCs) in vitro. The results showed that EPL could significantly induce the secretion of chemokines (RANTES and MCP-1), promote the production of nitric oxide and induced nitric oxide synthase, improve the pinocytic and phagocytic activity of KCs, promote the mRNA expression of TNF-α and IL-1β, and enhance the expression of costimulatory molecules (CD11b and CD68) in KCs compared with Epimedium polysaccharide-propolis flavone (EP) at 30–7.5μg/mL. In addition, the abilities of KCs on stimulating lymphocytes proliferation and antigen presenting were significantly enhanced after stimulated with EPL compared with EP. These results suggested that EPL could activate KCs and possessed the stronger immunomodulatory effect, which provided the theoretical basis for further studying the mechanism of EPL on improving the immune response.

Noninvasive imaging assessment of non-alcoholic fatty liver disease: Focus on liver scintigraphy

Noninvasive diagnoses of nonalcoholic fatty-liver disease (NAFLD) involve the use of serologic markers and imaging methods, such as conventional ultrasonography (US), computed tomography, and magnetic resonance imaging. Although these methods are reliable for the noninvasive detection of moderate to severe fatty changes in the liver, they are not reliable for detecting nonalcoholic steatohepatitis (NASH) and fibrosis. New imaging technologies, such as US-based transient elastography, acoustic radiation force impulse and magnetic resonance-based elastography, can reportedly be used to determine the severity of liver fibrosis associated with NASH. In this context, the field of nuclear medicine through liver scintigraphy has recently been proposed, and is being explored for use in the diagnosis of NASH. More importantly, nuclear medicine may contribute to the distinction between simple steatosis and NASH. For example, the enhanced release of cytokines and the decrease in the phagocytic activity of Kupffer cells play important roles in the pathogenesis of NASH. Removal of technetium-99m colloid from circulation by Kupffer cell phagocytosis therefore provides a valuable imaging technique. Thus, nuclear medicine is poised to provide useful tools for the evaluation of patients with NAFLD. However, the evidence is still scarce, and more studies with larger samples are needed to identify their role before they are used in clinical practice.

NADPH Oxidases in Chronic Liver Diseases.

Oxidative stress is a common feature observed in a wide spectrum of chronic liver diseases including viral hepatitis, alcoholic, and nonalcoholic steatohepatitis. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are emerging as major sources of reactive oxygen species (ROS). Several major isoforms are expressed in the liver, including NOX1, NOX2, and NOX4. While the phagocytic NOX2 has been known to play an important role in Kupffer cell and neutrophil phagocytic activity and inflammation, the nonphagocytic NOX homologues are increasingly recognized as key enzymes in oxidative injury and wound healing. In this review, we will summarize the current advances in knowledge on the regulatory pathways of NOX activation, their cellular distribution, and their role in the modulation of redox signaling in liver diseases.

The Effect of Synthetic C-Reactive Protein on the In Vitro Immune Response of Human PBMCs Stimulated with Bacterial Reagents

Synthetic C-reactive protein (CRP) rescues mice from lethal endotoxin shock or bacterial infection by suppressing tumor necrosis factor (TNF-α), but in turn, enhances Kupffer cell phagocytic activity. We herein assessed the influence of CRP in human peripheral blood mononuclear cells (PBMCs). When human PBMCs were stimulated in vitro with penicillin-treated Streptococcus pyogenes, bacterial DNA motifs and lipopolysaccharide with or without synthetic CRP, CRP suppressed the production of TNF-α and IL-12, but not that of IFN-γ. This was also the case for the in vitro Shwartzman reaction induced in PBMCs. CRP also decreased high-mobility group box 1 production from macrophages, which is crucial in the later phase of endotoxin/septic shock. However, CRP upregulated the perforin expression by CD56+ NK cells and increased their antitumor cytotoxicity. CRP may thus be a potent immunomodulatory factor in the human immune system, suggesting its therapeutic potential for use against human septic shock.

C(6)-ceramide enhances phagocytic activity of Kupffer cells through the production of endogenous ceramides.

Ceramide has been suggested to be not only a tumor-suppressive lipid but also a regulator of phagocytosis. We examined whether exogenous cell-permeable C(6)-ceramide enhances the phagocytic activity of Kupffer cells (KCs) and affects the level of cellular ceramides. Rat KCs were isolated by collagenase digestion and differential centrifugation, using Percoll system. Phagocytic activity was measured by FACS analysis after incubating KCs with fluorescence-conjugated latex beads, and the level of cellular ceramide was analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). In this study we found that permeable C(6)-ceramide increases the cellular levels of endogenous ceramides via a sphingosine-recycling pathway leading to enhanced phagocytosis by KCs.

The alterations in hepatic microcirculation and Kupffer cell activity after biliary drainage in jaundiced mice

The aim of this study is to examine the effects of biliary drainage on hepatic microcirculation and Kupffer cell activity in the liver with obstructive jaundice. Common bile duct ligation and division was performed on C57BL/6 mice to induce obstructive jaundice. Seven or 14 days after surgery, some mice underwent biliary drainage. Three days after biliary drainage, sinusoidal perfusion, leukocyte rolling and sticking in the postsinusoidal venules, and the diameters of sinusoids containing blood flow were evaluated using intravital microscopy. Kupffer cell phagocytic activity was estimated as the ratio of Kupffer cells that phagocytosed fluorescent-labeled particles to sinusoids containing blood flow. Sinusoidal perfusion after biliary drainage was significantly increased compared with that in livers with obstructive jaundice, but remained decreased compared with controls. Although the number of rolling leukocytes and sticking leukocytes was significantly decreased, the diameters of sinusoids remained reduced, associated with an increase in Kupffer cell phagocytic activity compared with controls even after biliary drainage. Leukocyte-endothelial cell interaction is ameliorated but sinusoids remain narrowed due to swelling of activated Kupffer cells; this might cause deterioration of hepatic microcirculation during the early phase of biliary drainage.

A primary study on the phagocytic activity of Kupffer cells with superparamagnetic iron oxide particles enhanced MR imaging in a rat nonalcoholic steatohepatitis model

Objective To investigate the feasibility of using superparamagnetic iron oxide(SPIO)as MRI contrast agent to assess rat nonalcoholic steatohepatitis Kupffer cells(KC)function.Methods Twenty male SD rats were randomly divided into A and B groups,group A(n=10)was the experimental group fed high fat diet,group B(n=10)was the control group fed normal diet After 8 weeks,plain MR and SPIO enhanced MR were performed in all the rats.Blood lipids were measured,and HE and Perl's blue staining in all livers specimen was done.The related results of the staining were analyzed with t test Results Group A TC and TG levels[(6.58±1.25)and(1.53±0.23)mmol/L respectively]were significantly higher than group B[(1.64±0.22)and(0.55±0.14)mmol/L respectively](t=11.716 and 11.588,P＜0.01).Group A and B groups hepatic signal intensity decreased in all sequences after SPIO enhanced,but in group A the level of decline[(34.78±4.51)% and(60.38±3.49)% respectively]was less than group B[(64.96±2.42)% and(81.08±1.66)% respectively]on PDWI and T_1WI,and statistically significant differences(t=-18.451 and-16.240,P＜0.01)were found.In group A the ratio of signal intensity of liver to spleen(1.002±0.141,5.000±0.516,20.004±1.490 and 2.601±0.077 respectively)was more than group B(0.400±0.102,1.500±0.115,0.503±0.105 and-0.300±0.058)before and after contrast enhancement on PDWI,T_2WI,T_2~* WI andT_1WI(t=10.745,19.800,39.168 and 92.785,P＜0.01).Typical histological hepatic lesions of NASH were observed in group A,Perl's staining-positive particles in group A(2.33±0.50)were fewer than in group B(4)(t=-10.000,P＜0.01).Conclusion The high-fat diet induced model of SD rats was close to the human NASH and was easy to establish.Clinical application of SPIO enhanced MR successfully assessed the phagocytic activity of KC in the study,and it suggested that the pathogenesis of NASH was related to the decreased phagocytic activity of KC. Key words: Fatty liver; Magnetic resonance imaging; Kupffer cells; Animal experimentation

Cardiac dysfunction induced by experimental myocardial infarction impairs the host defense response to bacterial infection in mice because of reduced phagocytosis of Kupffer cells

This study was undertaken to investigate the effects of cardiac dysfunction induced by experimental myocardial infarction on the host defense response to bacterial infection and the role of Kupffer cells in mediating this response. Myocardial infarction was induced in C57BL/6 mice by ligation of the left anterior descending coronary artery. Mice were challenged with Escherichia coli intravenously 1, 5, and 14 days after myocardial infarction or sham operation. Thereafter, the cytokine production and the function of their Kupffer cells were assessed. Mice with myocardial infarction showed remarkable cardiac dysfunction and had a significantly lower survival than sham mice after bacterial challenge at 5 days after surgery; bacterial challenge at 1 or 14 days after surgery resulted in no difference in survival between myocardial infarction and sham mice. The phagocytic activity of Kupffer cells, assessed by fluorescein isothiocyanate microspheres, remarkably decreased in mice with myocardial infarction 5 days after surgery. Serum peaks of tumor necrosis factor and interferon-gamma after bacterial challenge were also suppressed in mice with myocardial infarction at 5 days. Production of these cytokines and immunoglobulin-M from liver mononuclear cells was also impaired in mice with myocardial infarction. Enhancement of the phagocytic activity of Kupffer cells by C-reactive protein significantly improved survival after infection in mice with myocardial infarction, although neither interleukin-18 nor immunoglobulin-M treatment improved survival. Cardiac dysfunction induced by myocardial infarction renders mice susceptible to bacterial infection and increases mortality because of a reduced ability of Kupffer cells to clear infectious bacteria. C-reactive protein-enhanced phagocytic activity of Kupffer cells may improve the poor prognosis after bacterial infection in mice with myocardial infarction.

Novel mechanism of C-reactive protein for enhancing mouse liver innate immunity

Although C-reactive protein (CRP) is a representative acute-phase protein produced by hepatocytes, the role of CRP in liver innate immunity remains unclear. Using C57BL/6 mice, the present study investigated how CRP affects the functions of liver macrophages, Kupffer cells, and natural killer / natural killer T (NK/NKT) cells under various conditions, including Escherichia coli infection, septic shock, and multiorgan dysfunction induced by interleukin (IL)-12/lipopolysaccharide (LPS) (generalized Shwartzman reaction [GSR]), and LPS-induced lethal hepatitis in Propionibacterium acnes-primed mice. When mice were challenged with a lethal dose of E. coli, synthetic CRP peptide decreased the mortality without decreasing serum tumor necrosis factor (TNF), presumably by enhancing the phagocytic activity of Kupffer cells. Synthetic CRP greatly decreased the production of TNF and reactive oxygen species from Kupffer cells and thereby rescued mice after lethal LPS challenge. CRP also decreased the mortality from GSR and lethal hepatitis by inhibiting TNF production from Kupffer cells, especially phagocytosing Kupffer cells. However, interferon-gamma production from NK/NKT cells was generally not so affected. CRP reportedly binds to FcgammaRI and FcgammaRII, and the injection of anti-FcgammaRII/III Ab into mice abrogated TNF production from, but increased the phagocytic activity of, Kupffer cells. Furthermore, CRP pretreatment restored the decreased phagocytic activity of Kupffer cells in burn-injured mice and decreased TNF production by Kupffer cells and thereby inhibited mortality after sublethal E. coli infection. If CRP was injected into mice at 1 hour after lethal E. coli challenge, it slightly but significantly increased the survival rate. CRP thus enhances the phagocytosis of Kupffer cells but decreases their TNF production in a complex manner in which the pathway by way of FcgammaRII may be involved.

Fundamental Efforts toward the Development of a Therapeutic Cocktail with a Manifold Ameliorative Effect on Hepatic Ischemia/Reperfusion Injury

Ischemia/reperfusion injury is mediated by various mechanisms. The present study was designed to evaluate the effect of a multiple pharmacological approach toward ischemia/reperfusion injury reduction. The left liver lobe of Sprague-Dawley rats underwent normothermic ischemia for 90 minutes after a cocktail (glycine, taurine, alanine, arginine, and prednisolon) intravenous administration. Controls received normal saline. Liver injury (transaminases, histology) and cellular activation [Kupffer cell phagocytosis, production of tumor necrosis factor-alpha (TNFalpha), and prostaglandin E-2 (PGE(2))], as well as microcirculation and leukocyte-endothelial interaction (in vivo microscopy), were assessed. Whereas in controls a substantial increase of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase to 2,341+/-477, 1,442+/-262, and 1,973+/-73 U/L, respectively, was measured eight hours after reperfusion, the cocktail significantly reduced the increase of enzymes by 33-80% (P<0.05). Further, necrosis, index of liver damage, and index of leukocyte infiltration significantly decreased after the cocktail (P<0.05). Moreover, the cocktail improved acinar and sinusoidal perfusion, while the sinusoidal diameters, leukocyte-endothelial interaction, Kupffer cell phagocytic activity, and TNFalpha/PGE(2) serum levels were significantly reduced, the latter by 86% and to 1.64-fold, respectively. This study depicts that multifaceted pharmacological tackling of ischemia/reperfusion injury is feasible and protects rat liver tissue from warm ischemia/reperfusion injury.

The effects of SOCS-1 on liver endotoxin tolerance development induced by a low dose of lipopolysaccharide are related to dampen NF-κB-mediated pathway

Background Endotoxin tolerance is an important mechanism to maintain the homeostasis of liver. It was reported that suppressors of cytokine signalling-1 was a negative regulator of lipopolysaccharide-induced macrophages activation, however, the mechanism underlying endotoxin tolerance and suppressors of cytokine signalling-1 has not been fully elucidated. Aim Our aim here is to clarify whether suppressors of cytokine signalling-1 was involved in the mechanisms of endotoxin tolerance in liver through dampening nuclear factor-κB-mediated pathway. Methods Endotoxin tolerance models of C57BL/6J mice and isolated Kupffer cells were established by pretreating them with a low dose of lipopolysaccharide to observe the changes of suppressors of cytokine signalling-1 expression during endotoxin tolerance inducement. Moreover, a vector-based short hairpin RNA expression system was used to specifically inhibit suppressors of cytokine signalling-1 expression in RAW264.7 macrophage cells to further explore the role of suppressors of cytokine signalling-1 in endotoxin tolerance inducement. The expression of suppressors of cytokine signalling-1 was analysed by immunohistochemistry, reverse transcription-polymerase chain reaction and Western blotting, respectively. The responses to lipopolysaccharide were assessed by the activation of nuclear factor-κB and the production of tumour necrosis factor-α, which were analysed by ELISA. Results The histopathologic changes in the liver of the non-endotoxin tolerance group were more serious than those of the endotoxin tolerance group. The phagocytic activity of Kupffer cells were depressed and suppressors of cytokine signalling-1 expression in the endotoxin tolerance group obviously increased. Endotoxin tolerance also led to a hyporesponse of Kupffer cells to lipopolysaccharide with less activation of nuclear factor-κB, less production of tumour necrosis factor-α and more expression of suppressors of cytokine signalling-1 than those of non-endotoxin tolerance group. Moreover, the inhibitive effect was partly refracted in pSOCS-1-short hairpin RNA transfected RAW264.7 cells. Conclusions Endotoxin tolerance induced by lipopolysaccharide pretreatment was accompanied with upregulation of suppressors of cytokine signalling-1 and the silence of suppressors of cytokine signalling-1 by RNA interference obviously attenuated this inhibitive effect, indicating that the absence of suppressors of cytokine signalling-1 caused abnormal enhancement of inflammatory cytokine production and suppressors of cytokine signalling-1 was involved in endotoxin tolerance inducement through dampening nuclear factor-κB-mediated pathway. Therefore, suppressors of cytokine signalling-1 may be a new target for the clinical treatment of sepsis.

Decreased phagocytic activity of Kupffer cells in a rat nonalcoholic steatohepatitis model

To investigate Kupffer cell dynamics and phagocytic activity, using a rat nonalcoholic steatohepatitis (NASH) model. Male F344 rats were fed either a control diet or a choline-deficient L-amino acid-defined (CDAA) diet, followed by contrast enhanced ultrasonography (CEUS) using Levovist. The uptake of latex beads by the Kupffer cells was determined by fluorescent microscopy. The status of the Kupffer cells was compared between the two groups, using the immunohistochemical staining technique. After 4 or more wk of the CDAA diet, CEUS examination revealed a decrease in the signal intensity, 20 min after intravenous Levovist. Fluorescent microscopic examination showed that the uptake of latex beads by the Kupffer cells was reduced at week 1 and 2 in the study group, compared with the controls, with no further reduction after 3 wk. Immunohistochemical staining revealed no significant difference in the Kupffer cell counts between the control group and the CDAA group. CEUS examination using Levovist demonstrated reduced contrast effect and phagocytic activity in the liver parenchymal phase, although the Kupffer cell numbers were unchanged, indicating reduced phagocytic function of the Kupffer cells in the rat NASH model. We believe that CEUS examination using Levovist is a useful screening modality, which can detect NASH in fatty liver patients.

Basal Activity of Kupffer Cells Increases With Old Age

Age-related changes in Kupffer cell numbers and function may have important implications for systemic immune responses and hepatic function. We compared numbers of Kupffer cells in the hepatic sinusoids and phagocytic function of Kupffer cells in isolated perfused livers of young, middle-aged, and old rats. On light microscopy, the number of Kupffer cells per 29,500 mum(2) field increased with increasing age (young 2.0 +/- 0.2, n = 8; middle aged 3.3 +/- 0.3, n = 7; old 5.5 +/- 0.6, n = 7). After a single pass through the liver, the ratio of the fractional recovery of 500 nm polystyrene microspheres to that of sucrose decreased significantly with increasing age: young rats, 89 +/- 35% (n = 7); middle-aged rats, 58 +/- 18% (n = 9); and old rats, 49 +/- 24% (n = 10), suggesting increased Kupffer cell phagocytic activity. In old age, increased Kupffer cell numbers and activity were observed in the basal state.

Chinese herb Radix Polygoni Multiflori as a therapeutic drug for liver cirrhosis in mice

Liver regeneration not only plays a functional role in directing the restoration of liver mass after resection or injury, but also may have participated in effective therapy of liver cirrhosis. Additionally, hepatocyte growth factor (HGF) appears to be a factor of great importance in liver regeneration and attenuated progression of experimental liver cirrhosis. The aim of this study is to use Radix Polygoni Multiflori (POMU) extract, a Chinese herb traditionally used for liver-protective therapy, as a reagent for the evaluation of its potential medicinal use in liver cirrhosis. We used in vitro coculture system to show that POMU could promote the expression of HGF by hepatic nonparenchymal cells, consequently the proliferation of primary liver cells and phagocytic activity of Kupffer cells using fluorescein-labeled Escherichia coli as the target, and inhibit the proliferation of stellate cells. Using dimethylnitrosamine-induced liver cirrhosis animal, POMU even at 20 mg/(kg day) dosage, was illustrated to reverse the pathogenic progression of the disease, decrease the hydroxyproline content and increases the expression of HGF messenger RNA in liver tissue. The survival rate was significantly increased in the POMU-treated animal. In conclusion, our study showed the promise of POMU in the medicinal use for the treatment of liver cirrhosis.