| 11. |
- 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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| 12. |
- Liu, Qing, et al.
(författare)
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Roquinimex inhibits dextran sodium sulfate-induced murine colitis
- 2003
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 52:2, s. 64-68
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Roquinimex is a modulator of the immune system and has been shown to attenuate induction of several inflammatory and autoimmune diseases. The objective of the present study was to determine the efficacy of roquinimex in a model of murine colitis. Materials and methods: For this purpose, Balb/c mice were exposed to 5% dextran sodium sulfate (DSS) in the drinking water for five to six days. Roquinimex (300 mg kg(-1) day(-1)) was administered by subcutaneous (s.c.) injection 3 days prior to and throughout the treatment period with DSS. In separate experiments, 300 mg kg(-1) day(-1) of roquinimex was given therapeutically after initiation of DSS challenge. Results: DSS provoked clinical signs of colitis, reduced crypt height (CH) and increased mucosal damage score (MDS) as analyzed by histology. In addition, challenge with DSS increased the colonic content of myeloperoxidase (MPO). Prophylactic administration of DSS-treated mice with roquinimex significantly reduced clinical signs of colitis, MDS and the CH-reduction. Moreover, in roquinimex treated animals, the MPO activity was significantly reduced by more than 50% compared to DSS control mice. Notably, therapeutic administration of roquinimex in DSS-treated mice also significantly inhibited the MDS, CH-reduction and MPO activity. Conclusions: These findings suggest that roquinimex strongly inhibits murine colitis and may provide a novel pharmacological approach to treat inflammatory bowel disease.
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| 13. |
- 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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| 14. |
- Muhammad, Asad, et al.
(författare)
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P-Selectin and P-Selectin Glycoprotein Ligand 1 Mediate Rolling of Activated CD8+ T Cells in Inflamed Colonic Venules.
- 2009
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Ingår i: Journal of Investigative Medicine. - 1708-8267. ; 57:7, s. 765-768
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Activated T cells regulate inflammatory diseases in the intestinal tract; however, the adhesive mechanisms governing CD8 T-cell recruitment in the colon are not known. METHODS:: Herein, we used a graft-versus-host disease (GvHD) model to study CD8 T-cell rolling and adhesion in the large intestine by use of intravital fluorescence microscopy. Graft-versus-host disease was induced by transferring 50 x 10 allogeneic donor splenocytes from BDF1, B6, H-2b mice to recipient BDF1, H-2 mice. After 8 days, rhodamine-labeled CD8 T cells (4 x 10) from healthy and GvHD mice were injected into both healthy and GvHD recipient mice, and CD8 T-cell-endothelium interactions were studied in the colon. RESULTS:: Activated CD8 T cells from GvHD mice expressed higher levels of P-selectin ligand and decreased levels of L-selectin. Immunoneutralization of P-selectin and P-selectin glycoprotein ligand 1 reduced CD8 T-cell rolling and adhesion in inflamed colonic venules by more than 71%. Inhibition of E-selectin had no effect on GvHD-induced CD8 T-cell-endothelium interactions. CONCLUSIONS:: We conclude that P-selectin and P-selectin glycoprotein ligand 1 are dominating molecules in supporting adhesive interactions of CD8 T cells in inflamed colonic venules and may be useful targets to protect against pathological inflammation in the large bowel.
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| 15. |
- Riaz, AA, et al.
(författare)
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Role of angiotensin II in ischemia/reperfusion-induced leukocyte-endothelium interactions in the colon
- 2004
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 18:3, s. 881-881
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Tidskriftsartikel (refereegranskat)abstract
- The aims of the present study were to determine the effects and mechanisms of angiotensin II (Ang II) on leukocyte-endothelium interactions and the role of Ang II in a novel model of ischemia/reperfusion (I/R) in the mouse colon. Ang II dose-dependently increased leukocyte rolling and adhesion in colonic venules. Importantly, Ang II-induced leukocyte rolling was completely inhibited by immunoneutralization of P-selectin, and leukocyte adhesion was abolished in lymphocyte function antigen-1 (LFA-1)-deficient mice. The P-selectin-dependent rolling was found to be a precondition for the subsequent LFA-1-dependent leukocyte adhesion. Moreover, Ang II-induced leukocyte responses involved generation of reactive oxygen species and up-regulation of CXC chemokines. Notably, CXC chemokines, but not Ang II, stimulated leukocyte chemotaxis in vitro. I/R increased gene expression of angiotensin converting enzyme (ACE) in the colon and plasma concentrations of Ang II. Inhibition of ACE and the type 1 angiotensin (AT(1)) receptor significantly decreased the I/R-induced leukocyte adhesion. Taken together, these novel findings demonstrate that Ang II exerts potent pro-inflammatory effects in the colonic microcirculation and that inhibition of Ang II expression or function protects against I/R-induced leukocyte responses in the colon. Thus, it is suggested that Ang II is a major target to control pathological inflammation in the colon.
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| 16. |
- Roller, Jonas, et al.
(författare)
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Direct in vivo observations of P-selectin glycoprotein ligand-1-mediated leukocyte-endothelial cell interactions in the pulmonary microvasculature in abdominal sepsis in mice.
- 2013
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 62:3, s. 275-282
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: P-selectin glycoprotein ligand-1 (PSGL-1) has been shown to play a significant role in septic lung injury. However, the detailed role of PSGL-1 in the pulmonary leukocyte recruitment remains elusive. We have developed a method based on intravital fluorescence microscopy of the lung microcirculation to examine the role of PSGL-1 in the extravasation process of leukocytes in septic lung damage. METHODS: Male C57BL/6 mice were treated with a control antibody or an anti-PSGL-1 antibody prior to cecal ligation and puncture (CLP). Leukocyte-endothelium interactions and microvascular hemodynamics were studied in pulmonary arterioles, capillaries and venules 4 h after CLP. RESULTS: Immunoneutralization of PSGL-1 decreased CLP-induced leukocyte rolling in pulmonary arterioles and venules significantly. Inhibition of PSGL-1 had no effect on leukocyte adhesion in venules, whereas the number of adherent leukocytes in lung arterioles and the number of trapped leukocytes in capillaries were markedly decreased. Moreover, immunoneutralization of PSGL-1 improved microvascular perfusion in the lung of septic animals. CONCLUSIONS: Taken together, these results document that PSGL-1 mediates leukocyte rolling in arterioles and venules. However, inhibition of PSGL-1 only decreases leukocyte adhesion in arterioles, suggesting that leukocyte rolling is not a prerequisite for pulmonary venular adhesion of leukocytes in sepsis. In addition, our data show that capillary trapping of leukocytes is dependent on PSGL-1 function.
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| 17. |
- Röme, Andrada, et al.
(författare)
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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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Ingår i: Diseases of the Colon & Rectum. - : Ovid Technologies (Wolters Kluwer Health). - 0012-3706. ; 50:12, s. 2194-2202
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Tidskriftsartikel (refereegranskat)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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| 18. |
- Santén, Stefan, et al.
(författare)
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Mast-cell-dependent secretion of CXC chemokines regulates ischemia-reperfusion-induced leukocyte recruitment in the colon.
- 2008
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Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 1432-1262 .- 0179-1958. ; 23, s. 527-534
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Recruitment of leukocytes in the tissue microvasculature is considered to be a rate-limiting step in ischemia-reperfusion (I/R)-induced inflammation. The objective of this study was to examine the role of mast cells in CXC-chemokine- and I/R-provoked leukocyte recruitment in the colon. MATERIALS AND METHODS: Balb/c- and mast-cell-deficient mice were challenged with the CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC) for 3 h. Leukocyte-endothelium interactions in the colonic microvascular bed were analyzed using an inverted intravital fluorescence microscopy technique. In separate experiments, mice were subjected to I/R by clamping of the superior mesenteric artery for 30 min followed by 120 min of reperfusion. RESULTS: MIP-2 and KC induced a clear-cut increase in the number of rolling and adherent leukocytes in the colon. I/R increased the expression of MIP-2 and KC as well as leukocyte rolling and adhesion in the large bowel. Interestingly, leukocyte rolling and adhesion was reduced by more than 91% in mast-cell-deficient mice in response to CXC chemokine challenge. Moreover, I/R-induced leukocyte rolling and adhesion was decreased by more than 57% in mast-cell-deficient animals. Administration of MIP-2 increased the colonic expression of E-selectin mRNA in wild type but not in mast-cell-deficient mice. CONCLUSION: Our data demonstrate that CXC chemokine-induced leukocyte rolling and adhesion is regulated by mast cells. Moreover, these findings also show that mast cells play a crucial role in supporting I/R-induced leukocyte rolling and adhesion in the colonic microvascular bed via secretion of CXC chemokines.
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| 19. |
- Santén, Stefan, et al.
(författare)
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P-selectin glycoprotein ligand-1 regulates chemokine-dependent leukocyte recruitment in colonic ischemia-reperfusion.
- 2007
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 56:11, s. 452-458
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Tidskriftsartikel (refereegranskat)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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| 20. |
- Santén, Stefan, et al.
(författare)
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Rho-kinase signalling regulates CXC chemokine formation and leukocyte recruitment in colonic ischemia-reperfusion.
- 2010
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Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 1432-1262 .- 0179-1958. ; 25, s. 1063-1070
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Leukocyte recruitment is a key feature in ischemia-reperfusion (I/R)-induced tissue injury. The aim of the present study was to investigate the effect of Rho-kinase inhibition on I/R-provoked leukocyte recruitment in the colon. METHODS: C57BL/6 mice were subjected to 30 min of ischemia by clamping of the superior mesenteric artery followed by 120 min of reperfusion. Intraperitoneal pretreatment with the selective Rho-kinase inhibitors fasudil (4-40 mg/kg) and Y-27632 (1-10 mg/kg) was administered prior to induction of colonic I/R. Leukocyte-endothelium interactions were analyzed by intravital fluorescence microscopy. Colonic content of tumour necrosis factor-alpha (TNF-alpha) and the CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC) were determined by ELISA. Additionally, colonic activity of myeloperoxidase (MPO), a marker of leukocyte infiltration, and malondialdehyde (MDA), were quantified. RESULTS: Fasudil and Y-27632 pretreatment decreased I/R-induced leukocyte rolling and adhesion by 76% and 96%, respectively. Moreover, Rho-kinase interference reduced formation of TNF-alpha, MIP-2 and KC by more than 68% in the reperfused colon. Additionally, the reperfusion-provoked increase in the levels of MPO and MDA in the colon decreased after Rho-kinase inhibition by 69% and 42%, respectively. CONCLUSIONS: Our data demonstrate that inhibition of Rho-kinase activity decrease I/R-induced leukocyte rolling, adhesion and recruitment in the colon. Moreover, these findings show that Rho-kinase signalling regulates TNF-alpha and CXC chemokine formation as well as lipid peroxidation in the reperfused colon. Thus, targeting Rho-kinase signalling may be a useful strategy in order to protect against pathological inflammation in the colon.
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