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| 2. |
- Röme, Andrada, et al.
(författare)
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p38 Mitogen-activated protein kinase signalling regulates vascular inflammation and epithelial barrier dysfunction in an experimental model of radiation-induced colitis.
- 2010
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 97, s. 226-234
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Microvascular injury and epithelial barrier dysfunction are rate-limiting aspects in radiation enteropathy. This study examined the role of p38 mitogen-activated protein kinase (p38 MAPK) signalling in radiation-induced colitis in an experimental model. METHODS:: The p38 MAPK inhibitor SB239063 was administered to mice immediately before exposure to 20 Gy radiation. Leucocyte- and platelet-endothelium interactions in the colonic microcirculation were assessed by intravital microscopy. Levels of myeloperoxidase (MPO) and CXC chemokines (macrophage inflammatory protein (MIP) 2 and cytokine-induced neutrophil chemoattractant (KC)), and albumin leakage were quantified 16 h after irradiation. RESULTS:: Irradiation induced an increase in leucocyte and platelet recruitment, MPO activity, CXC chemokine levels and intestinal leakage. Inhibition of p38 MAPK by SB239063 decreased radiation-induced leucocyte and platelet recruitment (leucocyte rolling and adhesion by 70 and 90 per cent, both P < 0.001; that of platelets by 70 and 74 per cent, both P < 0.001). It also reduced radiation-provoked increases in colonic MPO activity by 88 per cent (P < 0.001), formation of MIP-2 and KC by 72 and 74 per cent respectively (P = 0.003 and P < 0.001), and intestinal leakage by 81 per cent (P < 0.001). CONCLUSION:: p38 MAPK is an important signalling pathway in radiation-induced colitis. Copyright (c) 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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| 3. |
- Röme, Andrada, et al.
(författare)
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Radiation-induced platelet-endothelial cell interactions are mediated by P-selectin and P-selectin glycoprotein ligand-1 in the colonic microcirculation.
- 2012
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Ingår i: Surgery. - : Elsevier BV. - 1532-7361 .- 0039-6060. ; 151:4, s. 606-611
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Antiplatelet reagents have been reported to protect against intestinal damage associated with abdominal radiotherapy, but the mechanisms behind radiation-induced platelet-endothelium interactions are not known. We sought to define the adhesive mechanisms that regulate radiotherapy-induced platelet-endothelial cell interactions in the colon. METHODS: All mice except the controls were exposed to abdominal radiation with a single dose of 20 Gray. Mice were pretreated with an isotype-matched control antibody or a monoclonal antibody directed against either P-selectin or P-selectin glycoprotein ligand-1 (PSGL-1). Platelet and leukocyte rolling and adhesion in the colon were determined by use of inverted intravital fluorescence microscopy 16 hours after radiation. Radiation-induced intestinal leakage of fluorescein isothiocyanate-conjugated dextran was examined in separate experiments. RESULTS: Immunoneutralization of P-selectin decreased radiation-provoked platelet rolling by 87% and adhesion by 63%. Moreover, inhibition of PSGL-1 decreased platelet rolling and adhesion by 77% and 83%, respectively, in animals exposed to radiation. Similarly, inhibition of P-selectin and PSGL-1 decreased radiation-induced leukocyte rolling and adhesion by more than 84% and 90%, respectively, in the colon. In contrast, inhibition of P-selectin or PSGL-1 had no impact on radiation-induced intestinal leakage. In addition, systemic depletion of platelets and leukocytes did not affect intestinal barrier dysfunction in radiated animals. CONCLUSION: This study demonstrates that radiation-provoked platelet and leukocyte accumulation are mediated in part by P-selectin and PSGL-1. Radiation-induced gut leakage, however, is independent of accumulation of platelets and leukocytes in the intestinal microvasculature.
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| 4. |
- Röme, Andrada, et al.
(författare)
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Rho kinase signalling mediates radiation-induced inflammation and intestinal barrier dysfunction.
- 2011
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 98, s. 124-131
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Radiotherapy is important in the management of pelvic malignancies, but radiation-induced intestinal damage is a dose-limiting factor. Microvascular injury and epithelial barrier dysfunction are considered to be rate-limiting aspects in radiation-induced enteropathy. This study investigated the role of Rho kinase signalling in radiation-induced inflammation and intestinal barrier dysfunction. METHODS:: The specific Rho kinase inhibitor Y-27632 (1 and 10 mg/kg) was given to C57BL/6J mice before challenge with 20 Gy radiation. Leucocyte- and platelet-endothelium interactions in the colonic microcirculation were assessed by intravital microscopy. Levels of myeloperoxidase (MPO) and CXC chemokines (macrophage inflammatory protein 2 and cytokine-induced neutrophil chemoattractant), and intestinal leakage were quantified after 16 h. RESULTS:: Radiation increased leucocyte and platelet recruitment, MPO activity, CXC chemokine production and intestinal leakage. Y-27632 significantly reduced radiation-induced leucocyte rolling and abolished adhesion; it also decreased platelet rolling and adhesion by 55 and 74 per cent respectively (P < 0·050). Inhibition of Rho kinase signalling significantly decreased radiation-provoked formation of CXC chemokines, MPO activity by 52 per cent, and intestinal leakage by 67 per cent (P < 0·050). CONCLUSION:: Rho kinase activity constitutes an important signalling mechanism in radiation-induced inflammation and intestinal barrier dysfunction. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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| 5. |
- 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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| 6. |
- 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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| 7. |
- Santén, Stefan, et al.
(författare)
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p38 MAPK regulates ischemia-reperfusion-induced recruitment of leukocytes in the colon.
- 2009
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Ingår i: Surgery. - : Elsevier BV. - 1532-7361 .- 0039-6060. ; 145:3, s. 303-312
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Our objective was to examine the role of p38 mitogen-activated protein kinase (MAPK) in ischemia-reperfusion (I/R)-induced recruitment or leukocytes in the colon. METHODS: C57/Bl6 mice were subjected to 30 minutes of ischemia by clamping the superior mesenteric artery followed by 2 hours of reperfusion. Animals were pretreated with the selective p38 MAPK inhibitors SB 239063 and SKF 86002 before induction of I/R. Leukocyte-endothelium interactions were quantified by use of intravital fluorescence microscopy. Additionally, the role of p38 MAPK in mast cell-generated tumor necrosis factor-alpha (TNF-alpha) as well as neutrophil adhesion and P-selectin expression were examined in vitro. RESULTS: SB 239063 and SKF 86002 decreased both I/R-provoked leukocyte rolling and adhesion by > 75%. Inhibition of p38 MAPK decreased dose-dependently the mast cell generated TNF-alpha production as well as TNF-alpha-induced expression of P-selectin and neutrophil adhesion on endothelial cells. CONCLUSION: We conclude that p38 MAPK regulates leukocyte rolling and adhesion in colonic I/R. Moreover, inhibition of p38 MAPK activity decreases formation of TNF-alpha and P-selectin-dependent leukocyte attachment to activated endothelial cells. Thus, our findings suggest that interference with the p38 MAPK signaling pathway could be an effective strategy to protect against I/R-induced inflammation in the colon.
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| 8. |
- 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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