| 1. |
- Berglund, Lisa, et al.
(författare)
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Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation
- 2007
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Ingår i: American Journal of Physiology: Cell Physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 292:3, s. 1167-1178
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Tidskriftsartikel (refereegranskat)abstract
- The calcineurin/nuclear factor of activated T cells ( NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. Confocal immunofluorescence and Western blot analysis revealed that endothelin-1 efficiently increases NFATc3 nuclear accumulation in native arteries. Endothelin-1 also stimulates NFAT-dependent transcriptional activity, as shown by a luciferase reporter assay. Both the agonist-induced NFAT nuclear accumulation and transcriptional activity were prevented by the calcineurin inhibitor CsA and by the novel NFAT blocker A-285222. Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. Furthermore, by using small interfering RNA-mediated reduction of NFATc3, we show that this isoform is involved in the regulation of cell proliferation. Protein synthesis in intact arteries was investigated using autoradiography of [S-35] methionine incorporation in serum-free culture. Inhibition of NFAT signaling did not affect overall protein synthesis or specifically the synthesis rates of major proteins associated with the contractile/cytoskeletal system. An intact contractile phenotype under these conditions was also shown by unchanged force response to depolarization or agonist stimulation. Our results demonstrate NFAT expression and activation in native human vessels and point out A-285222 as a powerful pharmacological blocker of NFAT signaling in the vasculature.
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| 2. |
- Börjesson, Anna, et al.
(författare)
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Early treatment with lexipafant, a platelet-activating factor-receptor antagonist, is not sufficient to prevent pulmonary endothelial damage after intestinal ischaemia and reperfusion in rats.
- 2002
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Ingår i: Digestive and Liver Disease. - 1590-8658. ; 34:3, s. 190-196
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Intestinal ischaemia-reperfusion can lead to pulmonary injury characterised by increased macromolecular leakage and leukocyte sequestration. Important mediators of ischaemia-reperfusion-associated injury include polymorphonuclear granulocytes and platelet-activating factor. AIM: To investigate the potential therapeutic inhibition of platelet-activating factor in intestinal ischaemia-reperfusion associated pulmonary injury, by use of a potent platelet-activating factor-receptor antagonist, lexipafant. METHODS: Rats were subjected to 30 minutes of intestinal ischaemia followed by 3 or 12 hours reperfusion. Lexipafant or saline was given intraperitoneally after 30 minutes reperfusion. RESULTS: Increased leakage of radiolabelled human serum albumin was found in the lungs after intestinal ischaemia followed by 3 or 12 hours reperfusion. Administration of lexipafant did not significantly prevent the increased leakage. Pulmonary myeloperoxidase content increased after intestinal ischaemia-reperfusion, indicating polymorphonuclear granulocyte sequestration through the pulmonary endothelium. The increase in interleukin-1beta seen after 3 hours reperfusion was partly reversed by lexipafant. CONCLUSIONS: Pulmonary injury occurred following intestinal ischaemia-reperfusion, characterised by increased leakage of radiolabelled albumin over the endothelial barrier; correlating with increased pulmonary myeloperoxidase-content, implying involvement of polymorphonuclear granulocytes in the pathogenesis of remote organ injury after intestinal ischaemia-reperfusion. Lexipafant did not significantly decrease severity of pulmonary damage.
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| 3. |
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| 4. |
- Ederoth, Per, et al.
(författare)
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Experimental pancreatitis causes acute perturbation of energy metabolism in the intestinal wall
- 2002
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Ingår i: Pancreas. - 0885-3177. ; 25:3, s. 270-276
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The systemic inflammatory response syndrome (SIRS) may be initiated by a number of underlying conditions such as acute pancreatitis. The association between the local inflammatory reaction, the systemic response, and potential concomitant dysfunction of remote organs is not quite clear. Aim: To evaluate whether severe acute pancreatitis in the rat affects energy metabolism in the pancreas and whether the focal inflammation also causes biochemical deterioration in remote organs such as the liver and intestine. Methodology: With the patient under general anesthesia, microdialysis probes were inserted in the pancreas, liver, and small intestine. Two groups of eight rats each were studied: the sham (control) group and the pancreatitis group. Acute pancreatitis was induced by intraductal injection of 5% sodium taurodeoxycholate, and the animals were studied for 3 hours thereafter. The microdialysis fluid was analyzed for glucose, lactate, and pyruvate. Results: In the pancreatitis group we found significant increases in glucose concentration in the pancreas and lactate levels in the pancreas and intestinal wall, and the lactate/pyruvate ratio was significantly higher in the intestine than in the sham group. Conclusion: Induction of severe acute pancreatitis results in immediate metabolic alterations in the pancreas. In the intestinal wall a severe perturbation of energy metabolism is observed after only 1 hour. This implies a rapid onset of metabolic disturbances, not only in the local, challenged organ (pancreas) but also in remote organs.
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| 5. |
- Haraldsen, Pernille, et al.
(författare)
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Pancreatitis-associated pulmonary injury - effects of Lexipafant, a PAF-antagonist
- 2006
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Ingår i: Journal of Organ Dysfuntion. - : Informa UK Limited. - 1747-1060 .- 1747-1079. ; 2:1, s. 53-64
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Pulmonary injury is an important determinant of outcome in severe acute pancreatitis. The aim of this experimental study was to investigate the potential effect of lexipafant, a platelet-activating factor (PAF) antagonist, on pancreatitis-associated pulmonary injury in experimental acute pancreatitis. Material and methods. Acute pancreatitis was induced by intraductal infusion of 5% sodium taurodeoxycholate in rats that were given the PAF antagonist lexipafant either before (pretreatment) or after (treatment) induction of pancreatitis. Pulmonary endothelial barrier permeability, oedema, protease inhibitor levels, pulmonary ultrastructure and membrane system integrity and levels of interleukin-1 and -6 were evaluated. Results. Pulmonary injury was characterized by increased pulmonary endothelial barrier permeability, alveolar oedema and hypoxaemia, which were noted 12 h after the induction of pancreatitis. Pretreatment with lexipafant counteracted the increase in endothelial permeability and partially prevented derangements of protease inhibitor levels. Treatment with lexipafant reduced the severity of pulmonary endothelial barrier dysfunction and diminished the pancreatitis-induced increase in cytokines. Conclusions. PAF seems to play a major role in experimental pancreatitis-associated pulmonary injury and protease inhibitor imbalance. Treatment with a PAF inhibitor may ameliorate pancreatitis-associated pulmonary injury.
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| 6. |
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| 7. |
- Olanders, Knut, et al.
(författare)
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The effect of intestinal ischemia and reperfusion injury on ICAM-1 expression, endothelial barrier function, neutrophil tissue influx, and protease inhibitor levels in rats.
- 2002
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Ingår i: Shock. - 1540-0514. ; 18:1, s. 86-92
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Tidskriftsartikel (refereegranskat)abstract
- Multiple organ dysfunction syndrome (MODS) is mediated by complex mechanisms in which interactions between activated leukocytes and endothelial cells play a central role. ICAM-1 (intercellular adhesion molecule-1) mediates firm adhesion and transendothelial migration of activated leukocytes from postcapillary venules into the tissue. The present study evaluated the ICAM-1 expression in various organs after 40 min of intestinal ischemia and 1, 3, 6, 12 h of reperfusion (I/R) in the rat, using a dual monoclonal antibody technique (n = 36). Endothelial barrier permeability, using the vascular leakage of radiolabeled human serum albumin was also assessed (n = 12). Neutrophil sequestration in the lungs was quantitated by myeloperoxidase activity and plasma protease inhibitor levels were measured with electroimmunoassay. Significant regional differences were found in ICAM-1 expression between organs, both constitutively and after I/R-injury. The highest constitutive levels were observed in the liver and lungs, followed by the kidneys. The constitutive ICAM-1 expression in the intestines and in the heart was about 1/20 compared with that found in the liver and lungs. The brain and muscle had levels of about 1/150 of that in the liver and lungs. After intestinal I/R, significant increases (17-45%) were found in the lungs, intestines, brain, heart, and muscle. Albumin leakage index (ALI) in all examined organs and myeloperoxidase activity in the lungs increased after I/R-injury. Serum levels of albumin and most protease inhibitors decreased significantly after I/R challenge. Intestinal I/R results in an increase of systemic ICAM-1 expression with marked organ variability. The upregulation of ICAM-1 could represent a crucial step in the adherence- and migration process of activated leukocytes and potentially in the development of tissue injury.
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| 8. |
- Sun, Zhengwu, et al.
(författare)
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Effective treatment of gut barrier dysfunction using an antioxidant, a PAF inhibitor, and monoclonal antibodies against the adhesion molecule PECAM-1.
- 2002
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 105:2, s. 220-233
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oxygen free radicals (OFRs), platelet activating factor (PAF), cell adhesion molecules, and transmigration of polymorphonuclear leukocytes through the gut barrier are probably all essential in the development of gut barrier dysfunction following intestinal ischemia and reperfusion (I/R). Pretreatment and early treatment of I/R with the OFRs-scavenger (NAC), the PAF inhibitor lexipafant, and monoclonal antibodies against the adhesion molecule PECAM-1 (anti-PECAM-1-Mab) have been reported to be effective in the prevention or recovery of gut barrier dysfunction and result in a decrease in cytokine levels. Less is known about the effect of treatment inserted during the late stage of I/R. The objective of this study was to evaluate the potential therapeutic value of single or combination therapy with NAC, lexipafant, and anti-PECAM-1-MAb administered late during intestinal I/R in the rat. METHODS: NAC, lexipafant, and anti-PECAM-1-MAb were administrated, alone or in combination, after 3 h of reperfusion following 40 min of superior mesenteric arterial ischemia in the rat. Intestinal endothelial and epithelial barrier permeability, myeloperoxidase (MPO) activity, interleukin-1 beta (IL-1 beta), and protease inhibitor levels were evaluated after 12 h of reperfusion. RESULTS: Intestinal endothelial and epithelial permeability significantly increased in rats with I/R and saline treatment. Proteolytic activity in plasma was indicated by low levels of the three measured plasma protease inhibitors. Intestinal mucosal MPO content increased significantly. These changes were, to different degrees, reduced by late inserted treatment with NAC, lexipafant, or anti-PECAM-1-MAb. Alterations in systemic levels of IL-1 beta paralleled the changes found in gut barrier permeability and leukocyte trapping. Systemic antithrombin III levels and increased barrier permeability in remote organs were partly restored, especially by multimodal therapy. CONCLUSION: Treatment with NAC, lexipafant, and/or monoclonal antibodies against PECAM-1, inserted at a later stage of I/R, reduced the severity of I/R-associated intestinal dysfunction and decreased the systemic concentrations of IL-1 beta, local leukocyte recruitment (MPO), and partly restored plasma protease inhibitor levels.
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| 9. |
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| 10. |
- Sun, Zhengwu
(författare)
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Intestinal Ischemia and Reperfusion Injury - Pathophysiology as basis for novel treatment
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Intestinal ischemia and reperfusion (I/R) is not infrequent in the clinical situation and the intestinal barrier plays an important role in gut barrier function, preventing not at least septic complications and potentially the development of the multiple organ dysfunction syndrome. Mechanisms of intestinal I/R induced gut epithelial and endothelial barrier dysfunction and remote organ dysfunction, as well as potential preventive and therapeutic modes of management were evaluated in the rat. A short period of intestinal ischemia (20 min) was followed by an early epithelial barrier recovery as compared to longer (40 min) ischemia and same time period of reperfusion, though without obvious recovery of endothelial barrier permeability. Following the longer period of ischemia, no increased incidence of apoptosis and composition of epithelial DNA could be found. Intestinal I/R induced epithelial and endothelial barrier and remote organ dysfunction seemed to be the result not only from oxygene free radicals (OFRs), but also by other effects of over-activated phagocytic cells, cytokines like interleukin-1beta and 6, platelet-activating factor (PAF), imbalance of the protease- antiprotease system (including alfa1-macroglobulin, alfa2-antiplasmin, antithrombin III, prekallikrein, factor X) and effects depending on adhesion molecules such as ICAM-1 and PECAM-1. Pretreatment and treatment both at the early and late stage of I/R with OFR-scavengers, the antioxidant NAC, the PAF inhibitor lexipafant, and monoclonal antibodies against ICAM-1 or PECAM-1 were effective in reversing the otherwise occurring changes found like gut barrier dysfunction with increased barrier permeability, increased ileal MPO activity and bacterial translocation, consumption of protease inhibitors, and increased systemic levels of cytokines. Conclusion: Activated phagocytes, OFRs, cytokines, PAF, adhesion molecules, and imbalance in the protease-antiprotease system all seems involved in intestinal I/R induced gut endothelial and epithelial barrier as well as remote organ dysfunction. Treatment with NAC, lexipafant and/or monoclonal antibodies against PECAM-1 inserted before reperfusion or at both early or later stages of I/R were effective in reducing the changes that otherwise ocurrred after intestinal I/R.
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