Progressive development of a Th1-type hepatic cytokine profile in rats with experimental cholangitis

Tjandra, Kartika; Sharkey, Keith A.; Swain, Mark G.

doi:10.1002/hep.510310204

Cited by 68 publications

(47 citation statements)

References 38 publications

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“…Vehicle-treated mice fed ANIT diet for 2 weeks developed liver injury characterized by multifocal acute hepatocellular coagulative necrosis and inflammation (six of seven mice), mild peribiliary fibrosis, and moderate lymphocytic inflammation/bile duct epithelial hyperplasia (seven of seven mice) (Fig. 2, A and B), in agreement with previous studies (Tjandra et al, 2000;Lesage et al, 2001;Sullivan et al, 2010). Treatment with TA reduced liver necrosis and inflammation in mice fed ANIT diet (Fig.…”

Section: Resultssupporting

confidence: 90%

“…Transport of ANIT into the bile by hepatocytes injures intrahepatic BDECs (Dietrich et al, 2001), and exposure of mice to ANIT in the diet causes compensatory biliary hyperplasia, elevation in serum bile acids, portal lymphocytic inflammation, and mild to moderate hepatocellular injury (Tjandra et al, 2000;Xu et al, 2004;Sullivan et al, 2010;Golbar et al, 2013). Prolonged ANIT exposure in mice models progressive liver fibrosis characterized by exaggerated peribiliary collagen deposition (Tjandra et al, 2000;Xu et al, 2004;Sullivan et al, 2010;Golbar et al, 2013). BDEC injury in this model is associated with tissue factor-dependent activation of the blood coagulation cascade and increased plasma levels of the coagulation protease thrombin (Sullivan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

Joshi

Kopec

Towery

et al. 2014

J Pharmacol Exp Ther

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Hepatic fibrin deposition has been shown to inhibit hepatocellular injury in mice exposed to the bile duct toxicant a-naphthylisothiocyanate (ANIT). Degradation of fibrin clots by fibrinolysis controls the duration and extent of tissue fibrin deposition. Thus, we sought to determine the effect of treatment with the antifibrinolytic drug tranexamic acid (TA) and plasminogen activator inhibitor-1 (PAI-1) deficiency on ANIT-induced liver injury and fibrosis in mice. Plasmin-dependent lysis of fibrin clots was impaired in plasma from mice treated with TA (1200 mg/kg i.p., administered twice daily). Prophylactic TA administration reduced hepatic inflammation and hepatocellular necrosis in mice fed a diet containing 0.025% ANIT for 2 weeks. Hepatic type 1 collagen mRNA expression and deposition increased markedly in livers of mice fed ANIT diet for 4 weeks. To determine whether TA treatment could inhibit this progression of liver fibrosis, mice were fed ANIT diet for 4 weeks and treated with TA for the last 2 weeks. Interestingly, TA treatment largely prevented increased deposition of type 1 collagen in livers of mice fed ANIT diet for 4 weeks. In contrast, biliary hyperplasia/inflammation and liver fibrosis were significantly increased in PAI-1 2/2 mice fed ANIT diet for 4 weeks. Overall, the results indicate that fibrinolytic activity contributes to ANIT diet-induced liver injury and fibrosis in mice. In addition, these proof-of-principle studies suggest the possibility that therapeutic intervention with an antifibrinolytic drug could form a novel strategy to prevent or reduce liver injury and fibrosis in patients with liver disease.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

Joshi

Kopec

Towery

et al. 2014

J Pharmacol Exp Ther

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“…LFA-1 (CD11a/CD18), Mac-1 (CD11b/ CD18), CD44 (Ly-24), and GR-1 (Ly-6G) expression were measured in circulating and in liver-infiltrating neutrophils in response to LPS using flow cytometry, as previously described (29). Extraction of neutrophils from the liver was performed, as described previously (30), adapted to neutrophil purification using Percoll gradient. Samples of 100 l of whole blood or 1 million liver-derived leukocytes were incubated with 1 g of FITC-conjugated mAb anti-GR-1, 3 g of PE-conjugated mAb against LFA-1 or CD44, and 3 g of PE-Cy5-conjugated against Mac-1 mAb or nonspecific isotype controls (all purchased from BD Biosciences) for 30 min at room temperature.…”

Section: Leukocyte Harvest For Flow Cytometry Analysismentioning

confidence: 99%

Selective Down-Regulation of Neutrophil Mac-1 in Endotoxemic Hepatic Microcirculation via IL-10

Menezes

Lee

Zhou

et al. 2009

The Journal of Immunology

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Hepatic neutrophil adhesion during endotoxemia is an integrin-independent, CD44-dependent process. Because integrins function in other endotoxemic vasculatures, we used spinning disk confocal intravital microscopy to assess whether LPS down-modulated integrin functions in sinusoids. First, we applied fMLP onto the liver surface, and compared it with systemic LPS administration. Local fMLP caused neutrophil adhesion, crawling, and emigration for at least 2 h. Surprisingly, the number of adherent and crawling neutrophils was markedly reduced in Mac-1−/− and ICAM-1−/− mice, but not in mice treated with anti-CD44 mAb. By contrast, systemic LPS injection induced a robust accumulation of neutrophils in sinusoids, which was dependent on CD44, but not on integrins. Strikingly, local fMLP could not induce any integrin-dependent adhesion in endotoxemic mice treated with anti-CD44 mAb, indicating that Mac-1-dependent neutrophil adhesion was inhibited by LPS. This response was localized to the hepatic microvasculature because neutrophils still adhered via integrins in brain microvasculature. ICAM-1/ICAM-2 levels were not decreased, but following LPS treatment, Mac-1 was down-regulated in neutrophils localized to liver, but not in the circulation. Mac-1 down-regulation in neutrophils was not observed in IL-10−/− mice. In vitro neutrophil incubation with IL-10 induced direct decrease of Mac-1 expression and adhesivity in LPS-stimulated neutrophils. Therefore, our data suggest that Mac-1 is necessary for neutrophil adhesion and crawling during local inflammatory stimuli in sinusoids, but during systemic inflammation, neutrophils are exposed to high concentrations of IL-10, leading to a CD44-dependent, integrin-independent adhesion. This may be a mechanism to keep neutrophils in sinusoids for intravascular trapping.

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“…For this, individual perfused livers were homogenized in cold PBS buffer containing protease mixture inhibitor (SigmaAldrich) immediately after their removal as previously described (33). Tissue homogenates were centrifuged twice, and the supernatants were filtered through a 0.45-m filter, and stored at Ϫ80°C until used for determination of CCL2/MCP-1 and cytokine levels by ELISA, and total protein concentration using a Bio-Rad protein colorimetric assay (Bio-Rad Laboratories).…”

Section: Chemokine and Cytokine Elisasmentioning

confidence: 99%

“…The isolation of liver-infiltrating lymphocytes was conducted as previously described (33). Briefly, mice were pretreated with anti-MCP-1 antiserum (0.5 ml/mouse) or NRS as described in CCL2/MCP-1 neutralization.…”

Section: Isolation Of Liver-infiltrating Lymphocytesmentioning

confidence: 99%

C-C Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Directly Inhibits NKT Cell IL-4 Production and Is Hepatoprotective in T Cell-Mediated Hepatitis in the Mouse

Ajuebor

Hogaboam

et al. 2003

The Journal of Immunology

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T cell-mediated liver diseases are associated with elevated serum levels of C-C chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1). However, the extent to which the actions of CCL2/MCP-1 contribute to the pathogenesis of T cell-mediated hepatitis remains incompletely understood. Con A-induced hepatitis is a liver-specific inflammation mediated by activated T cells and is driven by an up-regulation of the hepatic expression of TNF-α, IFN-γ, and IL-4. The present study examined the role of CCL2/MCP-1 in the pathogenesis of T cell-mediated hepatitis induced by Con A administration in the mouse. We demonstrate a novel hepatoprotective role for CCL2/MCP-1 during Con A-induced hepatitis, because CCL2/MCP-1 neutralization strikingly enhanced hepatic injury, both biochemically and histologically, after Con A administration. Furthermore, CCL2/MCP-1 neutralization was associated with a significant reduction in the hepatic levels of TNF-α and IFN-γ, but with a significant increase in hepatic IL-4 levels. Moreover, IL-4 production and CCR2 expression by Con A-stimulated CD3+NK1.1+ T cells was significantly reduced by rMCP-1 treatment in vitro. In summary, we propose that CCL2/MCP-1 fulfills a novel anti-inflammatory role in T cell-mediated hepatitis by inhibiting CD3+NK1.1+ T cell-derived IL-4 production through direct stimulation of its specific receptor CCR2. These findings may have direct clinical relevance to T cell-mediated hepatitis.

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Progressive development of a Th1-type hepatic cytokine profile in rats with experimental cholangitis

Cited by 68 publications

References 38 publications

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

Selective Down-Regulation of Neutrophil Mac-1 in Endotoxemic Hepatic Microcirculation via IL-10

C-C Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Directly Inhibits NKT Cell IL-4 Production and Is Hepatoprotective in T Cell-Mediated Hepatitis in the Mouse

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