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Träfflista för sökning "WFRF:(Hartman Magnusson Hannes) "

Sökning: WFRF:(Hartman Magnusson Hannes)

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1.
  • Hartman Magnusson, Hannes, et al. (författare)
  • P-selectin mediates neutrophil rolling and recruitment in acute pancreatitis.
  • 2012
  • Ingår i: British Journal of Surgery. - John Wiley and Sons Inc.. - 1365-2168. ; 99, s. 246-255
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The adhesive mechanisms regulating leucocyte-endothelium interactions in the pancreas remain elusive, but selectins may play a role. This study examined the molecular mechanisms mediating leucocyte rolling along the endothelium in the pancreas and the therapeutic potential of targeting the rolling adhesive interaction in acute pancreatitis (AP). METHODS: Pancreatitis was induced by retrograde infusion of 5 per cent sodium taurocholate into the pancreatic duct, repeated intraperitoneal administration of caerulein (50 µg/kg) or intraperitoneal administration of L-arginine (4 g/kg) in C57BL/6 mice. A control and a monoclonal antibody against P-selectin were administered before and after induction of AP. Serum and tissue were sampled to assess the severity of pancreatitis, and intravital microscopy was used to study leucocyte rolling. RESULTS: Taurocholate infusion into the pancreatic duct increased the serum level of trypsinogen, trypsinogen activation, pancreatic neutrophil infiltration, macrophage inflammatory protein (MIP) 2 formation and tissue damage. Immunoneutralization of P-selectin decreased the taurocholate-induced increase in serum trypsinogen (median (range) 17·35 (12·20-30·00) versus 1·55 (0·60-15·70) µg/l; P = 0·017), neutrophil accumulation (4·00 (0·75-4·00) versus 0·63 (0-3·25); P = 0·002) and tissue damage, but had no effect on MIP-2 production (14·08 (1·68-33·38) versus 3·70 (0·55-51·80) pg/mg; P = 0·195) or serum trypsinogen activating peptide level (1·10 (0·60-1·60) versus 0·45 (0-1·80) µg/l; P = 0·069). Intravital fluorescence microscopy revealed that anti-P-selectin antibody inhibited leucocyte rolling completely in postcapillary venules of the inflamed pancreas. CONCLUSION: Inhibition of P-selectin protected against pancreatic tissue injury in experimental pancreatitis. Targeting P-selectin may be an effective strategy to ameliorate inflammation in AP. Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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2.
  • Abdulla, Aree, et al. (författare)
  • Platelets play an important role in acute pancreatitis
  • 2010
  • Ingår i: 45th Congress of the European-Society-for-Surgical-Research,Geneva, Switzerland,2010-06-09 - 2010-06-12. - John Wiley and Sons Inc..
  • Konferensbidrag (refereegranskat)
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3.
  • Abdulla, Aree, et al. (författare)
  • Platelets regulate P-selectin expression and leukocyte rolling in inflamed venules of the pancreas
  • 2012
  • Ingår i: European Journal of Pharmacology. - Elsevier. - 1879-0712. ; 682:1-3, s. 153-160
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent data suggest that platelets regulate inflammatory changes and tissue damage in acute pancreatitis although the role of platelets in leukocyte-endothelium interactions in the pancreatic microcirculation is not known. The aim of this study was to define the impact of platelets on leukocyte rolling and adhesion in acute pancreatitis. Acute pancreatitis was induced in C57BL/6 mice by caerulein challenge. Mice were treated with an a anti-GP1b alpha (CD42b) antibody, which depletes platelets, or a control antibody before caerulein. Leukocyte rolling and adhesion were determined by the use of intravital fluorescence microscopy 18 h after the last dose of caerulein. In separate experiments, leukocyte-endothelium interactions were determined before and after administration of an anti-P-selectin, anti-PSGL-1 and a control antibody in mice with caerulein pancreatitis. Circulating platelet-neutrophil aggregates and pancreatic P-selectin mRNA were quantified 1 and 6 h respectively after caerulein challenge. Caerulein administration increased leukocyte and platelet interactions in the pancreatic microvasculature, increased tissue damage and expression of P-selectin mRNA in the pancreas as well as platelet-neutrophil complexes in the circulation. Notably, platelet depletion markedly reduced caerulein-provoked leukocyte rolling and adhesion in postcapillary venules. Interestingly, depletion of platelets significantly decreased caerulein-induced gene expression of P-selectin in the pancreas. Moreover, immunoneutralization of P-selectin and PSGL-1 abolished leukocyte rolling in the pancreatic venules triggered by caerulein. Our novel findings demonstrate that platelets regulate leukocyte rolling in acute pancreatitis via induction of P-selectin, which was critical in supporting leukocyte rolling in inflamed venules of the pancreas. (C) 2012 Elsevier B.V. All rights reserved.
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4.
  • Abdulla, Aree, et al. (författare)
  • Role of platelets in experimental acute pancreatitis.
  • 2011
  • Ingår i: British Journal of Surgery. - John Wiley and Sons Inc.. - 1365-2168. ; 98, s. 93-103
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND:: Platelets not only control thrombosis and haemostasis but may also regulate inflammatory processes. Acute pancreatitis (AP) is characterized by changes in both coagulation and proinflammatory activities. The role of platelets in AP is not yet known. METHODS:: AP was induced in C57BL/6 mice by repeated caerulein administration (50 µg/kg intraperitoneally). Mice received a platelet-depleting or control antibody before caerulein challenge. Neutrophil infiltration, myeloperoxidase (MPO) and macrophage inflammatory protein (MIP) 2 levels, acinar cell necrosis and haemorrhage in the pancreas, as well as serum amylase activity, were determined 24 h after caerulein injection. In an alternative model of pancreatitis, L-arginine (4 g/kg intraperitoneally) was given twice with an interval of 1 h and tissue samples were taken after 72 h [Correction added after online publication 29 September 2010: in the preceding sentence, 4 mg/kg was corrected to 4 g/kg]. RESULTS:: Caerulein administration increased acinar cell necrosis, neutrophil infiltration, focal haemorrhage and serum amylase levels. Platelet depletion reduced acinar cell necrosis, haemorrhage and serum amylase levels in AP. Depletion of platelets decreased caerulein-induced MPO levels and neutrophil recruitment in the pancreas. Platelet depletion abolished caerulein-induced MIP-2 generation in the pancreas and circulation. The effects of platelet depletion on necrosis, neutrophils and MPO levels were confirmed in L-arginine-induced pancreatitis. CONCLUSION:: Platelets play a crucial role in AP by regulating neutrophil infiltration, most likely mediated by MIP-2 production in the pancreas. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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6.
  • Awla, Darbaz, et al. (författare)
  • Rho-kinase signalling regulates trypsinogen activation and tissue damage in severe acute pancreatitis.
  • 2011
  • Ingår i: British Journal of Pharmacology. - The British Pharmacological Society. - 1476-5381. ; 162, s. 648-658
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose: Severe acute pancreatitis (SAP) is characterized by trypsinogen activation, infiltration of leucocytes and tissue necrosis but the intracellular signalling mechanisms regulating organ injury in the pancreas remain elusive. Rho-kinase is a potent regulator of specific cellular processes effecting several pro-inflammatory activities. Herein, we examined the role of Rho-kinase signalling in acute pancreatitis. Experimental approach: Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a Rho-kinase inhibitor Y-27632 (0.5-5 mg kg(-1) ) before induction of pancreatitis. Key results: Taurocholate infusion caused a clear-cut increase in serum amylase, pancreatic neutrophil infiltration, acinar cell necrosis and oedema formation in the pancreas. Levels of pancreatic myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2), trypsinogen activation peptide (TAP) and lung MPO were significantly increased, indicating local and systemic disease. Inhibition of Rho-kinase activity dose-dependently protected against pancreatitis. For example, 5 mg kg(-1) Y-27632 reduced acinar cell necrosis, leucocyte infiltration and pancreatic oedema by 90%, 89% and 58% respectively as well as tissue levels of MPO by 75% and MIP-2 by 84%. Moreover, Rho-kinase inhibition decreased lung MPO by 75% and serum amylase by 83%. Pancreatitis-induced TAP levels were reduced by 61% in Y-27632-treated mice. Inhibition of Rho-kinase abolished secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. Conclusions and Implications: Our novel data suggest that Rho-kinase signalling plays an important role in acute pancreatitis by regulating trypsinogen activation and subsequent CXC chemokine formation, neutrophil infiltration and tissue injury. Thus, these results indicate that Rho-kinase may constitute a novel target in the management of SAP.
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9.
  • Hartman Magnusson, Hannes (författare)
  • Trypsinogen and neutrophil activation in acute Pancreatitis
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Background and aims: Acute pancreatitis (AP) is a common condition characterized by premature protease activation, abdominal pain and leakage of pancreatic enzymes to the circulation. Approximately 10% develop systemic inflammation and persistent organ failure. Although persistent organ failure in AP is associated with considerable mortality, no therapies to moderate the disease are at hand. This is in part due to lacking knowledge of the basic pathophysiology. In this thesis, murine models of AP are utilised to investigate pathophysiological mechanisms in vivo. The aim was to explore specific regulatory mechanisms of innate immunity and their potential relationship to protease activation and severity in AP. Results and conclusions: The therapeutic potential of targeting leukocyte rolling adhesive interactions was investigated in paper I. P-selectin mediates leukocyte sequestration and tissue injury, but not protease activation in AP. Paper II addresses the role of Rho-signalling in AP. Rho-kinase inhibition reduced chemokine formation and protease activation in AP. Moreover, Rho-kinase inhibition attenuated pancreatitis-associated systemic inflammation, tissue injury and leukocyte recruitment to the pancreas and lungs. Paper III demonstrates that histone deacetylases (HDACs) regulate severity in pancreatitis. HDAC inhibition reduced pancreatitis-associated gene expression and trypsinogen activation in vitro. These observations were accompanied by reduced leukocyte recruitment and tissue injury of the pancreas and lungs. Formation of neutrophil extracellular traps (NETs) has been observed in septic conditions. In paper IV pancreatitis was demonstrated to provoke NET-formation. Moreover, NETs were found to play an integral part in AP, regulating local tissue destruction and systemic complications. Histones are suggested to be the principal mediators of these processes. In conclusion, this thesis provides new insights in crucial neutrophil functions such as navigation, cell-signalling, acetylation and cytotoxicity. Targeting these mechanisms might be of future value in the management of patients with AP.
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10.
  • Merza, Mohammed, et al. (författare)
  • Neutrophil Extracellular Traps Induce Trypsin Activation, Inflammation, and Tissue Damage in Mice with Severe Acute Pancreatitis.
  • 2015
  • Ingår i: Gastroenterology. - Elsevier. - 1528-0012. ; 149:7, s. 1920-1920
  • Tidskriftsartikel (refereegranskat)abstract
    • Neutrophils are involved in development of acute pancreatitis (AP), but it is not clear how neutrophil-induced tissue damage is regulated. In addition to secreting antimicrobial compounds, activated neutrophils eliminate invading microorganisms by expelling nuclear DNA and histones to form extracellular web-like structures called neutrophil extracellular traps (NETs). However, NETs have been reported contribute to organ dysfunction in patients with infectious diseases. We investigated whether NETs contribute to development of AP in mice.
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