Hepatic Macrophage Activation and the LPS Pathway in Patients With Alcoholic Hepatitis: A Prospective Cohort Study

Sandahl, Thomas Damgaard; Grønbæk, Henning; Møller, Holger Jon; Støy, Sidsel; Thomsen, Karen Louise; Dige, Anders; Agnholt, Jørgen; Hamilton-Dutoit, Stephen; Thiel, Steffen; Vilstrup, Hendrik

doi:10.1038/ajg.2014.262

Cited by 86 publications

(78 citation statements)

References 35 publications

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“…We have shown that inhibition of LPA1 by ki16425 reduced LPS-induced phosphorylation of I-κB, p38 MAPK, and Erk1/2, and cytokine release in mouse lung epithelial cells [11]. To examine if similar physiology may be active in the abdominal LPS model, we evaluated the effect of ki16425 on LPS-induced signaling and cytokine release in the hepatocyte cells HepG2 and macrophage cell line Raw264, as cell death or inflammatory responses of these cells contribute to the pathogenesis of liver failure (24–26). LPS-induced phosphorylation of PKCδ and p38 MAPK were attenuated by ki16425 in HepG2 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Here we show that ki16425 abrogates the association between LPA1 and CD14, a co-receptor of LPS. Liver macrophages are a likely source of injurious inflammatory mediators like IL-6 and KC (26). Our findings in the Raw264 (macrophage cell line) cells indicate that ki16425 diminishes robust LPS-induced inflammatory responses in Raw264, suggesting that ki16426 confers an anti-inflammatory and anti-apoptotic effect in both liver epithelia and macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Lysophosphatidic acid receptor 1 antagonist ki16425 blunts abdominal and systemic inflammation in a mouse model of peritoneal sepsis

Zhao

Wei

Weathington

et al. 2015

Translational Research

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Lysophosphatidic acid (LPA) is a bioactive lipid mediator of inflammation via the LPA receptors 1–6. We and others have previously described pro-inflammatory and pro-fibrotic activities of LPA signaling in bleomycin- or lipopolysaccharide (LPS)-induced pulmonary fibrosis or lung injury models. In this study, we investigated if LPA signaling plays a role in the pathogenesis of systemic sepsis from an abdominal source. We report here that antagonism of the LPA receptor LPA1 with the small molecule ki16425 reduces the severity of abdominal inflammation and organ damage in the setting of peritoneal endotoxin exposure. Pretreatment of mice with intraperitoneal ki16425 eliminates LPS-induced peritoneal neutrophil chemokine and cytokine production, liver oxidative stress, liver injury, and cellular apoptosis in visceral organs. Mice pretreated with ki16425 are also protected from LPS-induced mortality. Tissue myeloperoxidase activity is not affected by LPA1 antagonism. We have shown that LPA1 is associated with LPS co-receptor CD14, the association is suppressed by ki16425. LPS-induced phosphorylation of PKCδ and p38 MAPK in liver cells and IL-6 production in Raw264 cells are likewise blunted by LPA1 antagonism. These studies indicate that the small molecule inhibitor of LPA1, ki16425, suppresses cytokine responses and inflammation in a peritoneal sepsis model by blunting downstream signaling through the LPA1-CD14-TLR4 receptor complex. This anti-inflammatory effect may represent a therapeutic strategy for the treatment of systemic inflammatory responses to infection of the abdominal cavity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid receptor 1 antagonist ki16425 blunts abdominal and systemic inflammation in a mouse model of peritoneal sepsis

Zhao

Wei

Weathington

et al. 2015

Translational Research

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“…The data therefore point to the CD163-positive macrophage population as a potential therapeutic target to prevent progression of further liver damage in patients with NASH with increased caloric intake, although such medical therapy may not substitute dietary interventions. Furthermore, the macrophage-targeting principle with GCs or other anti-inflammatory drugs might also be relevant for other inflammatory diseases, including other liver diseases such as acute alcoholic hepatitis, which shares pathology with NASH and has a several-fold accumulation of CD163-positive macrophages in the liver 59, 60. This disease has high mortality and there is an imminent need for new targeted approaches 26 …”

Section: Discussionmentioning

confidence: 99%

Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes

Svendsen

Graversen

Etzerodt

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation of liver macrophages are suggested to be essential to disease progression. In the present study, we show that a low dose of an anti-CD163-IgG-dexamethasone conjugate targeting the hemoglobin scavenger receptor CD163 in Kupffer cells and other M2-type macrophages has a profound effect on liver inflammatory changes in rats on a high-fructose diet. The diet induced severe non-alcoholic steatohepatitis (NASH)-like changes within a few weeks but the antibody-drug conjugate strongly reduced inflammation, hepatocyte ballooning, fibrosis, and glycogen deposition. Non-conjugated dexamethasone or dexamethasone conjugated to a control IgG did not have this effect but instead exacerbated liver lipid accumulation. The low-dose anti-CD163-IgG-dexamethasone conjugate displayed no apparent systemic side effects. In conclusion, macrophage targeting by antibody-directed anti-inflammatory low-dose glucocorticoid therapy seems to be a promising approach for safe treatment of fructose-induced liver inflammation.

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“…Furthermore, LPS enhances ethanol-induced hepatic microvascular dysfunction, liver injury and apoptosis [14, 15, 16]. Acute and chronic alcohol intake increases portal and systemic LPS in patients and animal models of ALD and has a positive correlation with the severity of the disease [13,17]. Studies comparing the effects of portal and systemic LPS in ethanol-exposed animals strongly suggest a gut source of endotoxins in the pathogenesis of ALD [18].…”

Section: Introductionmentioning

confidence: 99%

Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice

et al. 2017

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Backgrounds & Aims Bacterially-derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. Methods Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis +/− IAP supplementation. Liver tissue was assessed for biochemical, inflammatory and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. Results Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase (ALT) compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. Conclusions IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.

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Hepatic Macrophage Activation and the LPS Pathway in Patients With Alcoholic Hepatitis: A Prospective Cohort Study

Abstract: The hepatic inflammation of human AH involves marked activation of hepatic macrophages, likely via the LPS pathway. Hepatic macrophages may thus present a target for biological therapy of AH.

Cited by 86 publications

References 35 publications

Lysophosphatidic acid receptor 1 antagonist ki16425 blunts abdominal and systemic inflammation in a mouse model of peritoneal sepsis

Lysophosphatidic acid receptor 1 antagonist ki16425 blunts abdominal and systemic inflammation in a mouse model of peritoneal sepsis

Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes

Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice

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