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

Tsujimoto, Tatsuhiro; Kawaratani, Hideto; Kitazawa, Toshiyuki; Hirai, Toshiko; Ohishi, Hajime; Kitade, Mitsuteru; Yoshiji, Hitoshi; Uemura, Mamoru; Fukui, Hiroshi

doi:10.3748/wjg.14.6036

Cited by 33 publications

(45 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although these models lack obesity and insulin resistance, two major characteristics of NASH in humans, the possible relation of Kupffer cells with inflammation, steatosis, and fibrosis may resemble the human NASH. We also demonstrated decreased Kupffer cell phagocytic activity in this model [27] . The possible Kupffer cell dysfunction characterized by decreased phagocytic activity and increased cytokine production should be investigated in future studies.…”

Section: Discussionmentioning

confidence: 64%

Innate immune reactivity of the liver in rats fed a cholinedeficient L-amino-acid-defined diet

Kawaratani¹,

Tsujimoto²,

Kitazawa³

et al. 2008

WJG

Self Cite

View full text Add to dashboard Cite

AIM:To investigate the innate immune reactivity of tumor necrosis factor-alpha (TNF-α), Toll-like receptor 4 (TLR4), and CD14 in the liver of non-alcoholic steatohepatitis (NASH) model rats. METHODS: Male F344 rats were fed a cholinedeficient L-amino-acid-defined (CDAA) diet. The rats were killed after 4 or 8 wk of the diet, and their livers were removed for immunohistochemical investigation and RNA extraction. The liver specimens were immunostained for TNF-α, TLR4, and CD14. The gene expressions of TNF-α , TLR4 , and CD14 were determined by reverse-transcriptase polymerase chain reaction (RT-PCR). Kupffer cells were isolated from the liver by Percoll gradient centrifugation, and were then cultured to measure TNF-α production. RESULTS: The serum and liver levels of TNF-α in the CDAA-fed rats increased significantly as compared with the control group, as did the immunohistochemical values and gene expressions of TNF-α, TLR4, and CD14 with the progression of steatohepatitis. TNF-α production from the isolated Kupffer cells of the CDAAfed rats was elevated by lipopolysaccharide stimulation. CONCLUSION: The expressions of TNF-α, TLR4, and CD14 increased in the NASH model, suggesting that TLR4 and CD14-mediated endotoxin liver damage may also occur in NASH.

show abstract

Section: Discussionmentioning

confidence: 64%

Innate immune reactivity of the liver in rats fed a cholinedeficient L-amino-acid-defined diet

Kawaratani¹,

Tsujimoto²,

Kitazawa³

et al. 2008

WJG

Self Cite

View full text Add to dashboard Cite

show abstract

“…Namely, it has been considered to represent the phagocytic activity of KCs. However, recent studies have reported that impairment of KC phagocytic activity is dependent on the level of activity in each KC and is not dependent on a reduction in the total number of KCs in studies of animal models of non-alcoholic steatohepatitis (29,30).…”

Section: Discussionmentioning

confidence: 99%

Correlation of Kupffer cell function and hepatocyte function in chronic viral hepatitis evaluated with superparamagnetic iron oxide-enhanced magnetic resonance imaging and scintigraphy using technetium-99m-labelled galactosyl human serum albumin

Tonan

Fujimoto

Qayyum

et al. 2011

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Kupffer cells contribute to the pathogenesis of liver injury in chronic liver disease, yet it is difficult to assess Kupffer cell function either ex vivo or in vivo, since supporting data are limited. The aim of this study was to clarify the relation between Kupffer cell function and hepatocyte function by analyzing the correlation between conventional indices of hepatic functional reserve and both superparamagnetic iron oxide-enhanced MRI (SPIO-MRI) and technetium-99m-galactosyl human serum albumin scintigraphy (Tc-99m-GSA) in patients with chronic viral hepatitis. Consecutive 46 patients (16 patients with chronic hepatitis and 30 patients with cirrhosis) who underwent both SPIO-MRI and Tc-99m-GSA were examined. The patients were aged 46-83 years (median 70) and included 29 men and 17 women. Spearman correlation coefficient was used to analyze the correlations between functional reserve indices and both reduction percentages of liver-to-muscle signal intensity ratio (reduction-%LMR), as a surrogate parameter of Kupffer cell function and Tc-99m-GSA parameters. The usefulness of each parameter as a marker to differentiate Child-Pugh A from Child-Pugh B/C was evaluated using receiver operating characteristic (ROC) analysis. The reduction-%LMR correlated more closely with Child-Pugh score (r=0.77; P<0.001) than did Tc-99m-GSA parameters. For predicting Child-Pugh B/C, ROC analysis revealed that reduction-%LMR (AUC=0.91, P<0.001) was the most useful parameter and at a cutoff value of 50% or less, sensitivity, specificity, positive and negative predictive values were 0.79, 0.91, 0.94 and 0.71, respectively. SPIO-MRI may be a helpful non-invasive method for the evaluation of hepatic functional reserve, and this study suggests that Kupffer cell function is closely correlated with hepatocyte function in patients with chronic viral hepatitis. IntroductionProper assessment of hepatic functional reserve is crucial to the selection of patients for hepatic surgery, particularly in liver transplantation and the management of liver cirrhosis. The Child-Pugh score (1,2) is now used worldwide as the standard in the assessment of hepatic functional reserve (3). Given the relation between this score and survival in patients with cirrhosis of the liver, it has recently been listed as one of the parameters in the minimal criteria of the liver transplant Abbreviations: SPIO, superparamagnetic iron oxide; Tc-99m-GSA-scintigraphy, scintigraphy using technetium-99m-labelled galactosyl human serum albumin; GRE, gradient-recalled echo; ROIs, regions of interest; %LMR, percentages of liver-to-muscle signal intensity ratio; H15, uptake ratio of the heart at 15 min after Tc-99m-GSA injection; H3, uptake ratio of the heart at 3 min after Tc-99m-GSA injection; HH15, index of blood clearance = H15/H3; L15, radioactivity of the liver at 15 min after Tc-99m-GSA injection; LHL15, the receptor index = L15/(H15 + L15); ICG15, indocyanine green retention rate at 15 min; ROC analysis, receiver operating characteristic analysisKey words: chro...

show abstract

“…Kupffer cells, part of the innate immune system, produce various cytokines and are known to play a role in pathologies of the liver [2,3] . Abnormally functioning Kupffer cells are suspected to be involved in NASH [4] . Although the etiological mechanisms of NASH have not been fully elucidated, similar histopathological findings in NASH and alcoholic hepatitis suggest the existence of a common underlying mechanism.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy for nonalcoholic steatohepatitis using themultiple cytokine production modulator Y-40138

Tsujimoto¹,

Kawaratani²,

Kitazawa³

et al. 2009

WJG

Self Cite

View full text Add to dashboard Cite

AIM:To investigate the possible use of the multiple cytokine production modulator, Y-40138, as a novel immunotherapy in the rat nonalcoholic steatohepatitis (NASH) model. METHODS:We allocated 6-wk-old male F344 rats to choline-supplemented, L-amino acid-defined (CSAA) diet (control group), CSAA diet + Y-40138 (control + Y-40138 group), choline-deficient, L-amino acid-defined (CDAA) diet (NASH group), or CDAA diet + Y-40138 (NASH + Y-40138 group). In each group, we measured the plasma alanine aminotransferase (ALT) levels, and the plasma and liver levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-10 (IL-10). Tissue specimens of phosphate buffered saline-perfused liver were subjected to hematoxylin and eosin staining, Azan staining, Sirius red staining, and immunohistochemical staining (for Kupffer cells and TNF-α). We then extracted Kupffer cells from the collagenase-perfused livers using the Percoll gradient centrifugation method, and measured the TNF-α levels in the supernatant (in vitro TNF-α production by Kupffer cells) using an enzyme-linked immunosorbent assay kit. RESULTS:In comparison to the NASH group, serum ALT elevation was mild, production of serum and liver TNF-α and IFN-γ was inhibited, and IL-10 production was increased in the NASH + Y-40138 group. Amelioration of liver histology was also noted in the NASH + Y-40138 group. Kupffer cell immunohistochemical staining revealed no differences between groups, whereas TNF-α immunohistochemical staining showed fewer stained cells in the NASH + Y-40138 group than in the NASH group. The TNF-α levels in the in-vitro Kupffer cell culture supernatant were lower in the NASH + Y-40138 group than in the NASH group. CONCLUSION:Administration of Y-40138 to NASH model rats reduced hepatic inflammation and suppressed fibrosis. These results indicate that the multiple cytokine production modulator, Y-40138, is promising as a novel treatment for NASH.

show abstract

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

Abstract: Abstract

Cited by 33 publications

References 28 publications

Innate immune reactivity of the liver in rats fed a cholinedeficient L-amino-acid-defined diet

Innate immune reactivity of the liver in rats fed a cholinedeficient L-amino-acid-defined diet

Correlation of Kupffer cell function and hepatocyte function in chronic viral hepatitis evaluated with superparamagnetic iron oxide-enhanced magnetic resonance imaging and scintigraphy using technetium-99m-labelled galactosyl human serum albumin

Immunotherapy for nonalcoholic steatohepatitis using themultiple cytokine production modulator Y-40138

Contact Info

Product

Resources

About