Inhibition of Toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection

The objective of this study was to elucidate the role of Toll-like receptor 4 (TLR4) in liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide (LPS) infusion in rats. Biliary obstruction often leads to the development of bacterial translocation. Rats were subjected to either a sham operation (Sham group) or bile duct ligation for 7 days (BDL group). Seven days after each operation, LPS (0.5 μg) was injected through the ileocecal vein. In other experiments, rats that had undergone BDL were pretreated, before LPS challenge, with internal biliary drainage (Drainage group); intravenous TAK-242, a TLR4 inhibitor (TAK group); or intravenous GdCl3, a Kupffer cell deactivator (GdCl3group). The expression of the TLR4 protein and the number of Kupffer cells in the liver were significantly increased in the BDL group compared with the Sham group. These changes were normalized after biliary drainage. The expression of TLR4 colocalized with Kupffer cells, which was confirmed by double immunostaining. Serum levels of liver enzymes and proinflammatory cytokines after intraportal LPS injection were significantly higher in the BDL group than in the Sham group. However, pretreatment with TAK-242 or GdCl3strongly attenuated these changes to levels similar to those seen with biliary drainage. These results imply that blocking TLR4 signaling effectively attenuates liver damage to the same level as that observed with biliary drainage in rats with BDL and subsequent intraportal LPS infusion. TAK-242 treatment may be used for patients who are susceptible to liver damage by biliary obstruction and endotoxemia.

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S-Adenosylmethionine attenuates lipopolysaccharide-induced liver injury by downregulating the Toll-like receptor 4 signal in Kupffer cells

Hepatology International ◽

10.1007/s12072-014-9528-6 ◽

2014 ◽

Vol 8 (2) ◽

pp. 275-284 ◽

Cited By ~ 8

Author(s):

Peizhi Li ◽

Zhao Zhang ◽

Jianping Gong ◽

Yan Zhang ◽

Xiwen Zhu

Keyword(s):

Liver Injury ◽

Kupffer Cells ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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The Effects of L-Arginine on Liver Damage in Experimental Acute Cholestasis an Immunohistochemical Study

HPB Surgery ◽

10.1155/2011/306069 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 11

Author(s):

Yucel Ozsoy ◽

Mustafa Ozsoy ◽

Teoman Coskun ◽

Kemal Namlı ◽

Ahmet Var ◽

...

Keyword(s):

Liver Injury ◽

Liver Damage ◽

Biliary Obstruction ◽

Hepatic Tissue ◽

Control Group ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Duct Ligation ◽

And Control ◽

Acute Cholestasis

Obstructive jaundice damages critical functions in the liver. Nitric oxide modulation would influence liver damage induced by biliary obstruction, and little is known about it Acute cholestasis was induced by bile duct ligation (BDL) in two groups of male Sprague-Dawley rats. L-Arginine or serum physiologic was administered to treatment and control group. Histopathological and immunohistochemical iNOS expression was investigated in hepatic tissue. Plasma enzyme activities were increased in acute cholestasis, and that L-arginine treatment partially but significantly prevented the elevation of these markers of liver damage (P< .05). Also histopathology scoring showed that the liver injury was prevented and immunohistochemical iNOS activity was increased significantly in L-arginine group (P< .05). This study shows that, after 7 days of biliary obstruction, liver damage is well established and exogenous L-arginine treatment partially but significantly prevented the liver injury in acute cholestasis.

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Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00550.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. G256-G265 ◽

Cited By ~ 294

Author(s):

Grace L. Su

Keyword(s):

Liver Injury ◽

Proinflammatory Cytokines ◽

Kupffer Cells ◽

Cell Activation ◽

Molecular Mechanisms ◽

Binding Protein ◽

Toll Like Receptor ◽

Lipopolysaccharide Binding Protein ◽

Toll Like Receptor 4 ◽

Lipopolysaccharide Binding

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.

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The Therapeutic Potential of Toll‐like Receptor 4 Antagonists in Preventing Liver Injury Induced by Biliary Obstruction and Subsequent Endotoxemia

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.1004.1 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Yukihiro Yokoyama ◽

Shingo Oya ◽

Toshio Kokuryo ◽

Masato Nagino

Keyword(s):

Liver Injury ◽

Biliary Obstruction ◽

Therapeutic Potential ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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MicroRNA 181b-3p and its target importin α5 regulate toll-like receptor 4 signaling in Kupffer cells and liver injury in mice in response to ethanol

Hepatology ◽

10.1002/hep.29144 ◽

2017 ◽

Vol 66 (2) ◽

pp. 602-615 ◽

Cited By ~ 31

Author(s):

Paramananda Saikia ◽

Damien Bellos ◽

Megan R. McMullen ◽

Katherine A. Pollard ◽

Carol de la Motte ◽

...

Keyword(s):

Liver Injury ◽

Kupffer Cells ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Liver histological, portal flow and plasmatic nitric oxide alterations caused by biliary obstruction and drainage in rats

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502008000700002 ◽

2008 ◽

Vol 23 (suppl 1) ◽

pp. 2-7 ◽

Cited By ~ 1

Author(s):

Miguel Angel Dias ◽

Reginaldo Ceneviva ◽

Jorge Elias Jr. ◽

Sergio Zucoloto ◽

Caroline Floreoto Baldo ◽

...

Keyword(s):

Bile Duct ◽

Biliary Obstruction ◽

Bile Duct Ligation ◽

Sham Operation ◽

Portal Flow ◽

Histological Alterations ◽

Duct Occlusion ◽

Duct Ligation ◽

Male Wistar Rats ◽

Periodic Evaluation

PURPOSE: To evaluate liver alterations caused by biliary obstruction and drainage. METHODS: Thirty-nine male Wistar rats were randomly distributed in 4 groups: BO (n=18) bile duct ligation for 20 days, with a periodic evaluation of liver histological alterations, Doppler echography portal flow and measurements of NO and malondialdehyde (MDA); BO/DB (n=13) bile duct occlusion for 20 days followed by biliary drainage by choledochoduodenal anastomosis, 5 days follow-up, same BO group parameters evaluations; group CED (n=4) sham operation and portal flow evaluation trough 20 days; CHB (n=4) sham operation, with hepatic biopsy on 25th day and followed-up trough 25 days, by the same parameters of group BO, with exception of portal flow. Direct bilirubin (DB) and alkaline phosphatase (AP) were evaluated in the group BO, BO/DB and CHB. RESULTS: The bile duct ligation led to an increase of DB and AP, development of liver histological alterations, reduction of portal flow and increase of plasmatic NO and of MDA levels. The bile duct clearing resulted in a reduction of DB, AP, NO, MDA histological alterations and increase of portal flow. CONCLUSION: The biliary occlusion resulted in cholestasis and portal flow reduction, besides the increase of plasmatic NO and of hepatic MDA levels, and histological liver alterations, with a tendency of normalization after the bile duct clearing.

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Cell-specific regulatory effects of CXCR2 on cholestatic liver injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00080.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. G773-G783 ◽

Cited By ~ 2

Author(s):

Takanori Konishi ◽

Rebecca M. Schuster ◽

Holly S. Goetzman ◽

Charles C. Caldwell ◽

Alex B. Lentsch

Keyword(s):

Bile Duct ◽

Liver Injury ◽

Liver Damage ◽

Chemokine Receptor ◽

Therapeutic Target ◽

Bile Duct Ligation ◽

Wild Type ◽

Neutrophil Accumulation ◽

Duct Ligation ◽

Cholestatic Liver Injury

The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2−/− mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2−/− mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2−/− mice showed significantly less neutrophil accumulation in those injured areas. CXCR2Liver+/Myeloid+ and CXCR2Liver−/Myeloid− mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2Liver+/Myeloid+ mice suffered higher liver injury than CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid+; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid−) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury. NEW & NOTEWORTHY This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.

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