| 1. |
- Thorlacius, Karin, et al.
(författare)
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Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury.
- 2006
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 79:5, s. 923-931
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Tidskriftsartikel (refereegranskat)abstract
- Rho-kinase signaling regulates important features of inflammatory reactions. Herein, we investigated the effect and mechanisms of action of the Rho-kinase inhibitor fasudil in endotoxemic liver injury. C57/BL/6 mice were challenged with lipopolysaccharide (LPS) and D-galactosamine, with or without pretreatment with the Rho-kinase inhibitor fasudil. Six hours after endotoxin challenge, leukocyte-endothelium interactions in the hepatic microvasculature were studied by use of intravital fluorescence microscopy and tumor necrosis factor {alpha} (TNF-{alpha}); CXC chemokines as well as liver enzymes and apoptosis were determined. Administration of fasudil reduced LPS-induced leukocyte adhesion in postsinusoidal venules and sequestration in sinusoids. Moreover, we found that fasudil abolished extravascular infiltration of leukocytes as well as production of TNF-{alpha} and CXC chemokines in the liver of endotoxemic mice. Liver enzymes and hepatocellular apoptosis were markedly reduced, and sinusoidal perfusion was improved significantly in endotoxemic mice pretreated with fasudil. Our novel data document that fasudil is a potent inhibitor of endotoxin-induced expression of TNF-{alpha} and CXC chemokines as well as leukocyte infiltration and hepatocellular apoptosis in the liver. Based on the present findings, it is suggested that inhibition of the Rho-kinase signaling pathway may be a useful target in the treatment of septic liver injury.
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| 2. |
- Dold, Stefan, et al.
(författare)
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Simvastatin protects against cholestasis-induced liver injury.
- 2009
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 156, s. 466-474
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis-induced liver inflammation and tissue damage. Experimental approach: C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg.kg(-1)) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined. Key results: Administration of 0.2 mg.kg(-1) simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37-82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL-induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg.kg(-1) simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation. Conclusions and implications: These findings show that simvastatin protects against BDL-induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.
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| 3. |
- Hakansson, A, et al.
(författare)
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Rose Hip and Lactobacillus plantarum DSM 9843 Reduce Ischemia/Reperfusion Injury in the Mouse Colon.
- 2006
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Ingår i: Digestive Diseases and Sciences. - : Springer Science and Business Media LLC. - 1573-2568 .- 0163-2116. ; 51:11, s. 2094-2101
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Tidskriftsartikel (refereegranskat)abstract
- schaemia/reperfusion (I/R) of the colon is an inflammatory condition that leads to tissue injury where reactive oxygen species play a central role. Rose hip is rich in biologically active polyphenols with antioxidative properties, which may be important in prevention of lipid peroxidation. L. plantarum DSM 9843 possesses enzymatic activity towards polyphenols. The objective of this study was to define the effect of oral administration of L. plantarum and rose hip in I/R injury. Administration of rose hip and L. plantarum significantly decreased MDA levels in caecum tissue and Enterobacteriaceae counts in caecum stool. A positive correlation between MDA levels and Enterobacteriaceae counts was found. The results support a synergistic/additive role of rose hip and L. plantarum in reducing lipid peroxidation. Therefore rose hip and L. plantarum may be used as a pretreatment to tissue injuries, e.g. colonic surgery, organ transplantation and vascular surgery.
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| 4. |
- Jeppsson, Bengt, et al.
(författare)
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Evidence-based medicine in HBP surgery: Is there any?
- 2005
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Ingår i: HPB. - : Elsevier BV. - 1477-2574 .- 1365-182X. ; 7:3, s. 197-200
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Tidskriftsartikel (refereegranskat)abstract
- Background. Evidence-based medicine (EBM) has become widely accepted as a basis for clinical decision in many fields of medicine. This review examines the specific role of EBM in hepato-biliary and pancreatic (HBP) surgery. EBM relies on four main sources, including clinical guidelines, meta-analyses, primary information and clinical experience. Randomized controlled trials (RCTs) constitute the cornerstone of EBM and a recent study reported that there are relatively few RCTs evaluating the effectiveness of surgical therapies and procedures (1,530 out of 45,342 or 3.4% in five leading surgical journals) and only a few in HBP surgery. Although the effort must be to implement EBM as far as possible in HBP surgery, there are several obstacles to conducting RCTs in HBP surgery, including problems associated with standardization of surgical skills, sham-operations often impossible to perform, and the general applicability of specific findings may be uncertain.Discussion. This paper will provide two relevant examples of EBM in HBP surgery in patients with hepatic metastases and pancreatic adenocarcinoma, illustrating some problems but also the potential of introducing EBM in HBP surgery. In the future, our effort must be devoted to implementing EBM in applicable areas of HBP surgery but also remembering that in certain areas accumulated knowledge from observational studies, including drainage of abscesses and surgical treatment of intestinal obstruction, may have similar or even higher clinical value than RCTs.
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| 5. |
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| 6. |
- Laschke, MW, et al.
(författare)
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Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis
- 2008
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 153:1, s. 148-156
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Tidskriftsartikel (refereegranskat)abstract
- Background:Although it is well known that extrahepatic cholestasis induces liver damage, the mechanisms are still not completely understood. The aim of the present study was to evaluate the role of platelets and P-selectin in cholestasis-induced liver injury.Experimental approach:C57BL/6 mice underwent bile duct ligation (BDL) and pretreatment with an anti-GP1balpha antibody, which depletes platelets, an anti-P-selectin antibody or a control antibody. Hepatic platelet and leukocyte recruitment as well as microvascular perfusion were determined by intravital fluorescence microscopy.Key results:BDL caused significant liver damage and sinusoidal perfusion failure. BDL further induced hepatic platelet accumulation with widespread intravascular platelet aggregates, increased platelet adhesion in postsinusoidal venules and massive platelet accumulation in liver sinusoids. Administration of the anti-GP1balpha antibody reduced systemic platelet count by 90%. Depletion of platelets in BDL mice not only abolished accumulation and adhesion of platelets in sinusoids and venules but also restored sinusoidal perfusion and reduced liver enzymes by more than 83%. Platelet depletion further reduced BDL-associated sinusoidal leukocyte accumulation by 48% although leukocyte-endothelium interactions in venules were not affected. Immunoneutralization of P-selectin also inhibited hepatic microvascular accumulation of platelets and leukocytes, and protected against cholestasis-provoked hepatocellular damage.Conclusions and implications:Platelets play an important role in BDL-induced liver injury by promoting leukocyte recruitment and deteriorating microvascular perfusion. Moreover, our findings demonstrate that cholestasis-induced accumulation of platelets is mediated by P-selectin. Thus, targeting platelet accumulation may be a useful strategy against liver damage associated with obstructive jaundice.British Journal of Pharmacology advance online publication, 19 November 2007; doi:10.1038/sj.bjp.0707578.
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| 7. |
- Laschke, Matthias, et al.
(författare)
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The Rho-kinase inhibitor Y-27632 inhibits cholestasis-induced platelet interactions in the hepatic microcirculation.
- 2009
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Ingår i: Microvascular Research. - : Elsevier BV. - 1095-9319 .- 0026-2862. ; 78, s. 95-99
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Tidskriftsartikel (refereegranskat)abstract
- Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. Emerging data suggest that platelets may play an important role in tissue damage and inflammation. Herein, we characterized the platelet response in cholestatic liver injury and evaluated the role of Rho-kinase signaling. For this purpose, C57BL/6 mice were treated with the Rho-kinase inhibitor Y-27632 (10 mg/kg) and vehicle before undergoing bile duct ligation (BDL) for 12 h. Platelet rolling and adhesion, formation of platelet aggregates as well as microvascular perfusion in the liver were analyzed using intravital fluorescence microscopy. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Administration of Y-27632 reduced the BDL-associated increase of ALT and AST by 95% and 89%, respectively. The inhibition of Rho-kinase also reduced cholestasis-induced platelet rolling and adhesion by more than 46% and 73% in postsinusoidal venules and platelet adhesion in sinusoids by 60%. In addition, Y-27632 decreased platelet aggregation in hepatic sinusoids and postsinusoidal venules by 69% and 81%. BDL caused a significant reduction of hepatic microvascular perfusion. Importantly, pretreatment with Y-27632 restored sinusoidal perfusion in cholestatic animals. Our findings demonstrate that Rho-kinase regulates multiple aspects of platelet interaction in the microcirculation of cholestatic animals. Moreover, inhibition of Rho-kinase signaling not only attenuates platelet responses but also maintains microvascular perfusion and protects against hepatocellular injury in cholestasis. Thus, targeting Rho-kinase signaling may be an effective way to protect against platelet-mediated liver injury in obstructive jaundice.
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| 8. |
- Laschke, Mattias W, et al.
(författare)
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Sepsis-associated cholestasis is critically dependent on P-selectin-dependent leukocyte recruitment in mice.
- 2007
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Ingår i: American Journal of Physiology: Gastrointestinal and Liver Physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 292, s. 1396-1402
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Tidskriftsartikel (refereegranskat)abstract
- Cholestasis is a major complication in sepsis although the underlying mechanisms remain elusive. The aim of this study was to evaluate the role of P-selectin and leukocyte recruitment in endotoxemia- associated cholestasis. C57BL/6 mice were challenged intraperitoneally with endotoxin ( 0.4 mg/ kg), and 6 h later the common bile duct was cannulated for determination of bile flow and biliary excretion of bromosulfophthalein. Mice were pretreated with an anti-P-selectin antibody or an isotype- matched control antibody. Leukocyte infiltration was determined by measuring hepatic levels of myeloperoxidase. Tumor necrosis factor-alpha and CXC chemokines in the liver was determined by ELISA. Liver damage was monitored by measuring serum levels of alanine aminotransferase and aspartate aminotransferase. Apoptosis was quantified morphologically by nuclear condensation and fragmentation using Hoechst 33342 staining. Endotoxin induced a significant inflammatory response with increased TNF-alpha and CXC chemokine concentrations, leukocyte infiltration, liver enzyme release, and apoptotic cell death. This response was associated with pronounced cholestasis indicated by a > 70% decrease of bile flow and biliary excretion of bromosulfophthalein. Immunoneutralization of P-selectin significantly attenuated endotoxin- induced leukocyte infiltration reflected by a > 60% reduction of hepatic myeloperoxidase levels. Interference with P-selectin decreased endotoxin- mediated hepatocellular apoptosis and necrosis, but did not affect hepatic levels of tumor necrosis factor-alpha and CXC chemokines. Of interest, inhibition of P- selectin restored bile flow and biliary excretion of bromosulfophthalein to normal levels in endotoxin- challenged animals. Our study demonstrates for the first time that P-selectin-mediated recruitment of leukocytes, but not the local production of proinflammatory mediators, is the primary cause of cholestasis in septic liver injury.
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| 9. |
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| 10. |
- Mangell, Peter, et al.
(författare)
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Critical role of P-selectin-dependent leukocyte recruitment in endotoxin-induced intestinal barrier dysfunction in mice.
- 2007
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 56:5, s. 189-194
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To define the importance of leukocyte recruitment in endotoxin-induced gut permeability. Materials and methods: 31 male C57BL/6 mice were challenged with lipopolysaccharide (LPS). Ileal permeability was measured in Ussing chambers and leukocyte-endothelium interactions studied with intravital fluorescence microscopy after 18 h. Results: LPS caused a clear-cut increase in leukocyte accumulation and intestinal permeability. Immunoneutralisation of P-selectin not only reduced leukocyte recruitment significantly (54% reduction) but also abolished endotoxin-induced intestinal leakage. Intestinal levels of pro-inflammatory chemokines increased markedly in response to LPS but were not influenced by inhibition of P-selectin in vivo. Conclusion: The present study shows not only that endotoxin-induced leukocyte recruitment is mediated by P-selectin but also that sepsis-associated intestinal leakage in the gut is largely regulated by leukocyte accumulation. Thus, our novel data demonstrate a critical link between P-selectin-dependent leukocyte recruitment and gut barrier failure in endotoxemia.
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