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- Abdulla, Aree, et al.
(författare)
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Role of platelets in experimental acute pancreatitis.
- 2011
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 98, s. 93-103
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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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- Hartman Magnusson, Hannes, et al.
(författare)
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P-selectin mediates neutrophil rolling and recruitment in acute pancreatitis
- 2012
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 99, s. 246-255
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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. © 2011 British Journal of Surgery Society Ltd.
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- 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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- 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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- Slotta, J E, et al.
(författare)
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Rho-kinase signalling mediates endotoxin hypersensitivity after partial hepatectomy.
- 2008
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; Jun 18, s. 976-984
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Excessive loss of functional liver mass results in hepatic dysfunction and is associated with an increased sensitivity to infection. This experimental study investigated the role of Rho-kinase in hepatectomy-induced sensitization to endotoxin. METHODS:: Male C57BL/6J mice underwent 68 per cent hepatectomy and were injected 24 h later with 100 microg Escherichia coli lipopolysaccharide (LPS). Simultaneously, animals received either fasudil or Y-27632 for Rho-kinase inhibition, or phosphate-buffered saline. Untreated hepatectomized animals served as positive controls and sham-operated animals as negative controls. Liver injury and inflammatory parameters were assessed 6 h after LPS challenge by serum alanine aminotransferase (ALT) levels, histomorphology and enzyme-linked immunosorbent assay. RESULTS:: Hepatectomy resulted in a significant susceptibility to LPS, as indicated by inflammatory leucocyte recruitment (mean(s.e.m.) 10(1) leucocytes per high-power field), hepatocellular disintegration (ALT 22.4(3.1) microkat/l) and apoptotic cell death (3.8(0.2) per cent). Rho-kinase inhibition reduced leucocytic infiltration by more than 33 per cent, abolished hepatocellular apoptosis entirely, and reduced tumour necrosis factor alpha expression by more than 48 per cent and CXC chemokine expression by more than 36 per cent. CONCLUSION:: Hepatectomy increased susceptibility to LPS by Rho-kinase-dependent mechanisms. Blocking Rho-kinase signalling decreased LPS-induced liver injury in hepatectomized mice. Copyright (c) 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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