| 11. |
- Li, Xiang, et al.
(författare)
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Lymphocyte function antigen-1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice
- 2004
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 141:4, s. 709-716
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Tidskriftsartikel (refereegranskat)abstract
- 1 Sepsis is associated with leukocyte activation and recruitment in the liver. We investigated the role of lymphocyte function antigen-1 (LFA-1) in endotoxin-induced leukocyte-endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene-targeted mice, blocking antibodies and a synthetic inhibitor of LFA-1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS)+D-galactosamine (Gal), and intravital microscopy of the liver microcirculation was conducted 6 h later. 2 The number of Firmly adherent leukocytes in response to LPS/Gal was reduced by 48% in LFA-1-deficient mice. Moreover, endotoxin-induced increases of apoptosis and enzyme markers of hepatocellular injury were decreased by 64 and 69-90%, respectively, in LFA-1-deficient mice. Furthermore, sinusoidal perfusion was improved in endotoxemic mice lacking LFA-1. 3 A similar protective pattern was observed in endotoxemic mice pretreated with an antibody against LFA-1. Thus, immunoneutralization of LFA-1 reduced endotoxin-induced leukocyte adhesion by 55%, liver enzymes by 64-66% and apoptosis by 42%, in addition to the preservation of microvascular perfusion. 4 Administration of a novel statin-derived inhibitor of LFA-1, LFA703, significantly decreased leukocyte adhesion (more than 56%) and the subsequent liver injury in endotoxemic mice. 5 Thus, this study demonstrates a pivotal role of LFA-1 in supporting leukocyte adhesion in the liver. Moreover, interference with LFA-1-mediated leukocyte adhesion protects against endotoxemic liver damage, and may constitute a potential therapeutic strategy in sepsis.
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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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Lactobacillus plantarum 299v inhibits Escherichia coli-induced intestinal permeability.
- 2002
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Ingår i: Digestive Diseases and Sciences. - 1573-2568. ; 47:3, s. 511-516
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this work was to investigate whether a probiotic bacterium, Lactobacillus plantarum 299v, could affect Escherichia coli-induced passage of mannitol across the intestinal wall. Sprague-Dawley rats were pretreated for one week by either tube feeding with L. plantarum 299v twice daily, free access to L. plantarum 299v by adding the bacterium in the drinking water, or negative control receiving regular feeding. Intestinal segments were mounted in Ussing chambers and the mucosa was exposed to control medium, E. coli, and L. plantarum 299v (alone or together). [14C]Mannitol was added as a marker of intestinal permeability and samples were taken from the serosal side. E. coli exposure induced a 53% increase in mannitol passage across the intestinal wall (P < 0.05). One week of pretreatment with L. plantarum 299v in the drinking water abolished the E. coli-induced increase in permeability. Tube feeding for one week or short-term addition of L. plantarum 299v in the Ussing chambers had no effect on the permeability provoked by E. coli challenge. Notably, L. plantanum 299v itself did not change the intestinal passage of mannitol. These data demonstrate that pretreatment with L. plantarum 299v, which is a probiotic bacterium, protects against E. coli-induced increase in intestinal permeability, and that L. plantarum 299v alone has no influence on the intestinal permeability. Thus, this study supports the concept that probiotics may exert beneficial effects in the gastrointestinal tract.
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| 14. |
- Menger, MD, et al.
(författare)
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Experimental models to study microcirculatory dysfunction in muscle ischemia-reperfusion and osteomyocutaneous flap transfer
- 2003
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Ingår i: Langenbeck's Archives of Surgery. - : Springer Science and Business Media LLC. - 1435-2451 .- 1435-2443. ; 388:5, s. 281-290
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Tidskriftsartikel (refereegranskat)abstract
- Background. During the past decade, experimental studies have provided convincing evidence that microcirculatory dysfunction plays a pivotal role in the manifestation of tissue injury in ischemia-reperfusion and osteomyocutaneous flap transfer. The study of the mechanisms of injury, however, requires sophisticated experimental in vivo models. With the use of microsurgical techniques, osteomyocutaneous flap transfer can successfully be performed in rat hind limbs, allowing in vivo fluorescent microscopic analysis of post-ischemic microcirculatory dysfunction in all tissues involved, including periosteum, striated muscle, subcutis and skin. The drawback of this "acute" model is that the period of analysis is restricted to a few hours only. Method. To overcome this limitation, the "chronic" dorsal skinfold chamber preparation, containing striated muscle and subcutis, can be used. This model allows one to study microcirculatory dysfunction after both tourniquet-induced and pressure-induced ischemia-reperfusion-induced tissue injury over a period of up to 3 weeks. Results. With the use of these models, recent investigations have demonstrated that ischemia-reperfusion and osteomyocutaneous flap transfer are associated with capillary perfusion failure (no-reflow), mediated by intravascular hemoconcentration, endothelial swelling and endothelin (ET)-1-mediated microvascular constriction. In addition, post-ischemic reperfusion provokes an inflammatory response (reflow paradox) in post-capillary venules, which is characterized by beta(2)-integrin-mediated and intercellular adhesion molecule (ICAM)-1-mediated leukocyte adhesion and vascular hyperpermeability, which results in interstitial edema formation. Treatment studies have produced evidence that isovolemic hemodilution and heat shock protein induction are successful in ameliorating capillary no-reflow, while blockade of adhesion molecules, inactivation of oxygen radicals and, also, induction of heat shock proteins, are capable of reducing the post-ischemic inflammatory response. Conclusion. These experimental results not only demonstrate the importance of the use of advanced in vivo methods to delineate pathophysiological mechanisms in complex disease models, but may also provide a basis for potential prospective randomized trials to test the benefit for the patient in the daily clinical routine.
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| 15. |
- Månsson, Peter, et al.
(författare)
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Anastomotic healing in the rat colon: comparison between a radiological method, breaking strength and bursting pressure.
- 2002
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Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 1432-1262 .- 0179-1958. ; 17:6, s. 420-425
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: While mechanical parameters (breaking strength, bursting pressure) are used to measure colonic anastomotic healing, reported values are inconsistent. This study developed a novel approach to study colonic anastomotic repair and compared it with mechanical methods. Methods and materials: We created standardized four- and eight-suture colonic anastomoses and performed contrast enemas in rats. Results: All eight-suture anastomoses were tight at completion. In contrast, all four-suture anastomoses leaked immediately after the operation, but the integrity increased progressively, and at 12 h all were closed. No changes in breaking strength were observed up to 3 days postoperatively, in contrast to anastomotic bursting pressure which increased progressively over the same period. Integrity and bursting pressure increased in parallel to the anastomotic content of myeloperoxidase (MPO), indicating that neutrophil infiltration is not detrimental in normal healing. Moreover, local irradiation, which enhanced MPO activity, did not increase leakage, suggesting that neutrophil accumulation per se has no effect on the integrity of colonic anastomosis. In addition, administration of 5-fluorouracil, which decreased anastomotic MPO levels, increased anastomotic leakage. Conclusion: We present a novel approach to study anastomotic healing using radiological examination. While bursting pressure appears to be suitable for measuring early anastomotic healing in the colon, we demonstrate that breaking strength is not sufficiently sensitive to be used in examination of early healing. Moreover, our data suggest that the acute inflammatory response and associated neutrophil recruitment in the anastomosis does not negatively affect healing in the rat colon.
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| 16. |
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| 17. |
- 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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| 18. |
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| 19. |
- Schramm, R, et al.
(författare)
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Leukocyte adhesion in aorta and femoral artery in vivo is mediated by LFA-1
- 2004
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 53:10, s. 523-527
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Cytokine-induced recruitment of leukocytes is an early feature during arterial injury and atherosclerotic plaque formation. The aim of this study was to analyze the role of the beta(2)-integrin lymphocyte function-associated antigen-1 (LFA- 1; CD11a/CD18) in cytokine-triggered firm leukocyte adhesion to arterial endothelium in vivo. Material and Methods: Intravital fluorescence microscopy was used to study leukocyte firm adhesion in the mouse aorta and femoral artery in response to combined local challenge with TNF-alpha and IL-1beta. Results: In wild-type (WT) mice, cytokine stimulation resulted in firm adhesion of 14.6 +/- 2.8 and 11.3 +/- 1.3 leukocytes/mm along the endothelium in the aorta and femoral artery (P < 0.05 vs. PBS-treated controls, n = 5-6). Notably, the number of firmly adherent leukocytes in aorta and femoral artery of cytokine-stimulated LFA-1-deficient animals was reduced by 54% and 92% indicating an important role of LFA-1 in leukocyte adhesion to arterial endothelium (P < 0.05 vs. controls, n = 5-6). In addition, pretreatment of WT mice with a monoclonal antibody (mAb) directed against murine LFA-1 attenuated the leukocyte adhesive response by 60% and 86% in aorta and femoral artery, respectively (P < 0.05 vs. control mAb-treated WT, n = 5-12). Conclusion: These novel data demonstrate that cytokine-induced firm leukocyte adhesion in the mouse aorta and femoral artery is LFA-1-dependent in vivo, which may implicate an important role for this β(2)-integrin leukocyte extravasation. in arterial injury and atherogenesis.
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| 20. |
- Schramm, R, et al.
(författare)
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Neutrophil recruitment in mast cell-dependent inflammation: inhibitory mechanisms of glucocorticoids
- 2004
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 53:12, s. 644-652
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Forskningsöversikt (refereegranskat)abstract
- Mast cells are strategically localized along the microvasculature in tissues in close contact with the external environment, such as the skin, lung and intestines. By releasing a multi-faceted spectrum of proinflammatory mediators, such as cytokines and chemokines, mast cells have the capacity to coordinate trafficking of leukocytes. Mast cells play a pathophysiological role in numerous inflammatory diseases as diverse as hypersensitivity reactions, ischemia/reperfusion injury and rheumatoid arthritis. On the other hand, mast cells act also as tissue sentinels and are critically involved in the host defensive response against microbial infection by stimulating neutrophil recruitment. Glucocorticoids are powerful agents frequently used in mast cell-dependent diseases, although the anti-inflammatory mechanisms of these compounds are not completely understood at present. In order to circumvent steroid-associated side-effects and develop more specific therapeutics, numerous studies have examined the mechanisms underlying glucocorticoid inhibition of mast cell-dependent neutrophil recruitment. Based on recent findings, it may be suggested that glucocorticoids selectively inhibit the expression and function of certain adhesion molecules and chemokines. This review summarizes current insights into the underlying mechanisms of mast cell-regulated tissue accumulation of neutrophils and the inhibitory effects of glucocorticoids.
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