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Sökning: WFRF:(Thorlacius Henrik) > (2010-2014) > Regnér Sara

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1.
  • Abdulla, Aree, et al. (författare)
  • CD40L is not involved in acute experimental pancreatitis
  • 2011
  • Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 659:1, s. 85-88
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent data suggest that platelets not only control thrombosis and hemostasis but may also regulate inflammatory processes such as acute pancreatitis. However, the specific role of platelet-derived mediators in the pathophysiology of acute pancreatitis is not known. Herein, we examined the role of CD40 ligand (CD40L, CD154) in different models of acute pancreatitis. Acute pancreatitis was induced by repetitive caerulein administration (50 mu g/kg, i.p.) or infusion of sodium taurocholate (5%-10 mu l) into the pancreatic duct in wild-type C578L/6 and CD40L-deficient mice. Neutrophil infiltration, myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2) levels, acinar cell necrosis, edema and hemorrhage in the pancreas as well as serum amylase activity and lung levels of MPO were quantified 24 h after induction of acute pancreatitis. Caerulein and taurocholate challenge caused a clear-cut pancreatic damage characterized by increased acinar cell necrosis, neutrophil infiltration, focal hemorrhage, edema formation as well as increased levels of serum amylase and MIP-2 in the pancreas and lung MPO and histological damage. Notably, CD40L gene-deficient animals exhibited a similar phenotype as wild-type mice after challenge with caerulein and taurocholate. Similarly, administration of an antibody directed against CD40L had no effect against acute pancreatitis. Our data suggest that CD40L does not play a functional role in experimental acute pancreatitis. Thus, other candidates than CD40L needs to be explored in order to identify platelet-derived mediators in the pathophysiology of acute pancreatitis. (C) 2011 Elsevier B.V. All rights reserved.
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  • 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 BV. - 1879-0712 .- 0014-2999. ; 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 neutrophils in the activation of trypsinogen in severe acute pancreatitis.
  • 2011
  • Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 90, s. 975-982
  • Tidskriftsartikel (refereegranskat)abstract
    • The relationship between inflammation and proteolytic activation in pancreatitis is an unresolved issue in pancreatology. The purpose of this study was to define the influence of neutrophils on trypsinogen activation in severe AP. Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. For neutrophil depletion, an anti-Gr-1 antibody was administered before pancreatitis induction. Administration of the anti-Gr-1 antibody reduced circulating neutrophils by 97%. Pancreatic TAP and serum amylase levels increased 2 h and 24 h after induction of pancreatitis. Neutrophil depletion reduced pancreatic TAP and serum amylase levels at 24 h but not at 2 h after pancreatitis induction. Pancreatic MPO and infiltration of neutrophils, as well as MIP-2 levels, were increased 24 h after taurocholate infusion. Two hours after taurocholate administration, no significant pancreatic infiltration of neutrophils was observed. Injection of the anti-Gr-1 antibody abolished MPO activity, neutrophil accumulation, and MIP-2 levels, as well as acinar cell necrosis, hemorrhage, and edema in the pancreas at 24 h. Moreover, taurocholate-provoked tissue damage and MPO activity in the lung were normalized by neutrophil depletion. Intravital fluorescence microscopy revealed a 97% reduction of leukocytes in the pancreatic microcirculation after administration of the anti-Gr-1 antibody. Our data demonstrate that initial trypsinogen activation is independent of neutrophils, whereas later activation is dependent on neutrophils in the pancreas. Neutrophils are critical in mediating pancreatic and lung tissue damage in severe AP.
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5.
  • Abdulla, Aree, et al. (författare)
  • Role of platelets in experimental acute pancreatitis.
  • 2011
  • Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 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)
  • Lymphocyte function antigen-1 regulates neutrophil recruitment and tissue damage in acute pancreatitis.
  • 2011
  • Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 163, s. 413-423
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose: Leucocyte infiltration is a rate-limiting step in the pathophysiology of acute pancreatitis (AP) although the adhesive mechanisms supporting leucocyte-endothelium interactions in the pancreas remain elusive. The aim of this study was to define the role of lymphocyte function antigen-1 (LFA-1) in regulating neutrophil-endothelium interactions and tissue damage in severe AP. Experimental approach: Pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in mice. LFA-1 gene-targeted mice and an antibody directed against LFA-1 were used to define the role of LFA-1. Key results: Taurocholate challenge caused a clear-cut increase in serum amylase, neutrophil infiltration, CXCL2 (macrophage inflammatory protein-2) formation, trypsinogen activation and tissue damage in the pancreas. Inhibition of LFA-1 function markedly reduced taurocholate-induced amylase levels, accumulation of neutrophils, production of CXC chemokines and tissue damage in the pancreas. Notably, intravital microscopy revealed that inhibition of LFA-1 abolished taurocholate-induced leucocyte adhesion in postcapillray venules of the pancreas. In addition, pulmonary infiltration of neutrophils was attenuated by inhibition of LFA-1 in mice challenged with taurocholate. However, interference with LFA-1 had no effect on taurocholate-induced activation of trypsinogen in the pancreas. Conclusions and Implications: Our novel data suggest that LFA-1 plays a key role in regulating neutrophil recruitment, CXCL2 formation and tissue injury in the pancreas. Moreover, these results suggest that LFA-1-mediated inflammation is a downstream component of trypsinogen activation in the pathophysiology of AP. Thus, we conclude that targeting LFA-1 may be a useful approach to protect against pathological inflammation in the pancreas.
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7.
  • Awla, Darbaz, et al. (författare)
  • Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis.
  • 2012
  • Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 91, s. 711-719
  • Tidskriftsartikel (refereegranskat)abstract
    • MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas. Treatment with the broad-spectrum inhibitor of MMPs, BB-94, markedly reduced activation of trypsinogen, levels of CXCL2, infiltration of neutrophils, and tissue damage in AP. Taurocholate challenge increased serum levels of MMP-9 but not MMP-2. Taurocholate-induced amylase levels, neutrophil accumulation, production of CXCL2, trypsinogen activation, and tissue damage in the pancreas were abolished in MMP-9-deficient mice. Moreover, secretions from activated neutrophils isolated from WT but not from MMP-9-deficient animals stimulated trypsinogen activation in acinar cells. Notably, rMMP-9 greatly enhanced activation of trypsinogen in acinar cells. These findings demonstrate that neutrophil-derived MMP-9 is a potent activator of trypsinogen in acinar cells and regulates pathological inflammation and tissue damage in AP.
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8.
  • Awla, Darbaz, et al. (författare)
  • NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice.
  • 2012
  • Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 143:5, s. 1352-1352
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND & AIMS: The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) in development of AP in mice. METHODS: We measured levels of myeloperoxidase and macrophage inflammatory protein-2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 h after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes. RESULTS: Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an L-arginine-induced model of AP. Reverse transcriptase PCR and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium; activation was prevented by the calcineurin blocker cyclosporine A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells. CONCLUSIONS: NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice, and might be a therapeutic target.
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10.
  • 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. - : Wiley. - 1476-5381 .- 0007-1188. ; 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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