| 1. |
- Laschke, Mattias W, et al.
(author)
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Sepsis-associated cholestasis is critically dependent on P-selectin-dependent leukocyte recruitment in mice.
- 2007
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In: American Journal of Physiology: Gastrointestinal and Liver Physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 292, s. 1396-1402
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Journal article (peer-reviewed)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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| 2. |
- Mangell, Peter, et al.
(author)
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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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In: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 56:5, s. 189-194
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Journal article (peer-reviewed)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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| 3. |
- Röme, Andrada, et al.
(author)
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Critical Role of P-Selectin and Lymphocyte Function Antigen-1 in Radiation-Induced Leukocyte-Endothelial Cell Interactions in the Colon.
- 2007
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In: Diseases of the Colon & Rectum. - : Ovid Technologies (Wolters Kluwer Health). - 0012-3706. ; 50:12, s. 2194-2202
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Journal article (peer-reviewed)abstract
- Purpose Radiation therapy is frequently used in treating different types of tumors, although associated with serious side effects, such as fibrosis and complicated diarrhea. This study was designed to define the adhesive mechanisms behind radiotherapy-induced leukocyte recruitment in the colon. Methods All mice, except control animals, were radiated with a single dose of 20 Gy. Mice were pretreated with an isotype-matched control antibody or a monoclonal antibody directed against P-selectin. In separate experiments, lymphocyte function antigen-1–deficient animals were used. Leukocyte rolling and firm adhesion were determined by use of inverted intravital fluorescence microscopy 16 hours after radiation. Results It was found that immunoneutralization of P-selectin reduced leukocyte rolling by 83 percent and adhesion by 87 percent in radiated mice. Moreover, radiation-induced leukocyte adhesion in LFA-1-deficient mice was decreased by 94 percent compared with wild-type animals. Conclusions This study demonstrates that leukocyte rolling is mediated by P-selectin and that firm leukocyte adhesion is supported by lymphocyte function antigen-1 in radiation-induced enteritis. Moreover, P-selectin-dependent leukocyte rolling is a precondition for subsequent leukocyte adhesion in radiation-induced intestinal injury. Thus, targeting P-selectin and/or lymphocyte function antigen-1 may protect against pathologic inflammation in the colon induced by radiotherapy.
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| 4. |
- Santén, Stefan, et al.
(author)
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P-selectin glycoprotein ligand-1 regulates chemokine-dependent leukocyte recruitment in colonic ischemia-reperfusion.
- 2007
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In: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 56:11, s. 452-458
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Journal article (peer-reviewed)abstract
- Objective and design: Leukocyte recruitment is a key feature in ischemia-reperfusion (I/R) -provoked tissue injury. This study evaluated the role of P-selectin-glycoprotein ligand-1 (PSGL-1) in CXC chemokine- and ischemia-reperfusion- induced leukocyte rolling and adhesion in the colon. Materials Balb/c mice were used in an inverted intravital fluorescence microscopy study of the microvascular bed in the colon. Treatment: Mice were challenged with macrophage inflammatory protein-2 (MIP-2) intraperitonally and leukocyte-endothelium interactions were analysed 3 h later. In separate experiments, mice were exposed to I/R by clamping of the superior mesenteric artery for 30 min and leukocyte rolling and adhesion were analysed after 120 min of reperfusion. Results: MIP-2 dose-dependently increased leukocyte rolling and adhesion in the colon. Pretreatment with an anti-PSGL-1 antibody reduced MIP-2-provoked leukocyte rolling and adhesion by more than 89%. I/R increased expression of MIP-2 as well as leukocyte rolling and adhesion. Immunoneutralization of PSGL-1 decreased reperfusion-induced leukocyte rolling by 85% and adhesion by 93% in colonic venules. Conclusions: Our data demonstrates that PSGL-1 is a dominant adhesion molecule supporting MIP-2- and I/R-provoked leukocyte rolling. Inhibition of PSGL-1 abolished leukocyte rolling and abrogated I/R-induced leukocyte adhesion in colonic venules. These findings suggest that targeting PSGL-1 may be an effective strategy to prevent I/R-induced inflammation in the colon.
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| 5. |
- Thorlacius, Henrik, et al.
(author)
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Role of chromoendoscopy in colon cancer surveillance in inflammatory bowel disease.
- 2007
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In: Inflammatory Bowel Diseases. - : Oxford University Press (OUP). - 1536-4844 .- 1078-0998. ; 13:7, s. 911-917
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Research review (peer-reviewed)abstract
- Inflammation in the intestine is a well-known risk factor for neoplastic changes in the mucosa. In fact, it has been shown that long-standing ulcerative colitis and colonic Crohn's disease have a significantly increased risk for developing colorectal cancer, although the estimates vary widely between studies. Conventional colonoscopy is effective in detecting polypoid changes in the mucosa. However, it is now generally accepted that neoplastic changes in colitis are frequently flat and depressed, which are easily missed by use of routine colonoscopy. The introduction of chromoendoscopy, especially in combination with magnifying endoscopy, has greatly advanced our means to detect and differentiate neoplastic lesions in the colorectum. Accumulating evidence-based data indicate that implementation of chromoendoscopy into colon cancer surveillance protocols for patients with inflammatory bowel disease is effective. However, the introduction of chromoendoscopy into surveillance programs requires meticulous training and further studies to compare the value of chromoendoscopy to newer endoscopic devices and techniques, such as narrow band imaging.
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