Role of hepatocytes in direct clearance of lipopolysaccharide in rats

Mimura, Yoshihiro; Sakisaka, Shotaro; Harada, Masaru; Sata, Michio; Tanikawa, Kyuichi

doi:10.1016/0016-5085(95)90765-3

Cited by 151 publications

(113 citation statements)

References 29 publications

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“…13 Interestingly, hepatocytes are involved in the clearance of LPS following their intraportal injection and Kupffer cells do not contribute to this activity. 14,15 The evidence that hepatocytes express CD14, which presents LPS to TLR-4, and that this expression is enhanced in the course of endotoxemia confirms the role of these cells in the clearance of LPS. 16 In this framework, recent studies support the hypothesis that TNF-a and IL-1b, released by TLR-4 bearing Kupffer cells in response to LPS stimulation, induce TLR-2 expression on hepatocytes, thus increasing their sensitivity to Grampositive products.…”

Section: Experimental Studiesmentioning

confidence: 89%

Review: The role of the liver in the response to LPS: experimental and clinical findings

Jirillo

Caccavo

Magrone

et al. 2002

Journal of Endotoxin Research

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The liver plays an important physiological role in lipopolysaccharide (LPS) detoxification and, in particular, hepatocytes are involved in the clearance of endotoxin of intestinal derivation. In experimental shock models, tumor necrosis factor (TNF)-a induces hepatocyte apoptosis and lethal effects are due to secreted TNF-a and not to cell-associated TNF-a. An exaggerated production of TNF-a has been reported in murine viral infections, in which mice become sensitized to low amounts of LPS and both interferon (IFN)-g and IFN-a/b are involved in the macrophage-induced release of TNF-a. The prominent role of LPS and TNF-a in liver injury is also supported by studies of ethanol-induced hepatic damage. In humans, evidence of LPS-induced hepatic injury has been reported in cirrhosis, autoimmune hepatitis, and primary biliary cirrhosis and a decreased phagocytic activity of the reticulo-endothelial system has been found in these diseases. The origin of endotoxemia in hepatitis C virus (HCV) infected patients seems to be multifactorial and LPS may be of exogenous or endogenous derivation. In endotoxemic HCV-positive patients responsive to a combined treatment with IFN-a/ribavirin (RIB), endotoxemia was no longer detected at the end of the therapeutic regimen. By contrast, 48% of the non-responders to this treatment were still endotoxemic and their monocytes displayed higher intracellular TNF-a and interleukin (IL)-1b levels than responders. Moreover, in responders, an equilibrium between IFN-g and IL-10 serum levels was attained. In the non-responders, serum levels of IL-10 did not increase following treatment. This may imply that an imbalance between T helper (Th) 1 and Th 2 derived cytokines could be envisaged in the non-responders.

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Section: Experimental Studiesmentioning

confidence: 89%

Review: The role of the liver in the response to LPS: experimental and clinical findings

Jirillo

Caccavo

Magrone

et al. 2002

Journal of Endotoxin Research

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“…Both Kupffer cells (49,50) and hepatocytes (9,(51)(52)(53) were shown to participate in LPS clearance. A specific pathway for LPS deacylation in Kupffer cells was identified (54).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

Deng

Scott

Loughran

et al. 2013

The Journal of Immunology

170

137

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The morbidity associated with bacterial sepsis is the result of host immune responses to pathogens, which are dependent on pathogen recognition by pattern recognition receptors, such as TLR4. TLR4 is expressed on a range of cell types, yet the mechanisms by which cell-specific functions of TLR4 lead to an integrated sepsis response are poorly understood. To address this, we generated mice in which TLR4 was specifically deleted from myeloid cells (LysMTLR4KO) or hepatocytes (HCTLR4KO) and then determined survival, bacterial counts, host inflammatory responses, and organ injury in a model of cecal ligation and puncture (CLP), with or without antibiotics. LysM-TLR4 was required for phagocytosis and efficient bacterial clearance in the absence of antibiotics. Survival, the magnitude of the systemic and local inflammatory responses, and liver damage were associated with bacterial levels. HCTLR4 was required for efficient LPS clearance from the circulation, and deletion of HCTLR4 was associated with enhanced macrophage phagocytosis, lower bacterial levels, and improved survival in CLP without antibiotics. Antibiotic administration during CLP revealed an important role for hepatocyte LPS clearance in limiting sepsis-induced inflammation and organ injury. Our work defines cell type–selective roles for TLR4 in coordinating complex immune responses to bacterial sepsis and suggests that future strategies for modulating microbial molecule recognition should account for varying roles of pattern recognition receptors in multiple cell populations.

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“…105 In comparison to KCs, hepatocytes are more able to clear LPS from systemic circulation, through its uptake and release into the bile, where TLR4, CD14, and myeloid differentiation (MD)-2 have an obligatory role for LPS uptake by hepatocytes. 106 Furthermore, TLR4/MyD88 signaling in hepatocytes has been shown to play a pivotal role during the early progression of high fructose diet induced NAFLD, in which free High-mobility group protein B1 (HMGB1) served as a Damage-associated molecular pattern molecules (DAMP) mediating TLR4 activation. 107 Hepatic stellate cells (HSCs) trans-differentiate from quiescent to active state under the influence of activators like platelet-derived growth factor (PDGF) and transforming growth factor b1 (TGF-b1) secreted by activated KC, infiltrating monocytes, platelets, and damaged hepatocytes.…”

mentioning

confidence: 99%

The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis

Sharma

Mitnala

Vishnubhotla

et al. 2015

Journal of Clinical and Experimental Hepatology

128

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Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed. ( J CLIN EXP HEPATOL 2015;5:147-158)

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Role of hepatocytes in direct clearance of lipopolysaccharide in rats

Cited by 151 publications

References 29 publications

Review: The role of the liver in the response to LPS: experimental and clinical findings

Review: The role of the liver in the response to LPS: experimental and clinical findings

Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis

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