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| 2. |
- Akbarshahi, Hamid, et al.
(författare)
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TLR4 dependent heparan sulphate-induced pancreatic inflammatory response is IRF3-mediated
- 2011
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 9:219
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Tidskriftsartikel (refereegranskat)abstract
- Background: Degraded extracellular matrix can stimulate the innate immune system via the Toll-Like Receptor-4 (TLR4). In the pancreas, syndecan-anchored heparan sulphate (HS) on the ductal epithelium can be cleaved off its protein cores by the proteases (trypsin and elastase) and potentially activate TLR4 signalling. Methods: To investigate this signalling event, a low sulphated HS (500 mu g/ml) was infused into the biliary-pancreatic duct of C57BL/6J wild-type mice. Phosphate buffered saline (PBS) and lipopolysaccharide (LPS) were used as negative and positive controls, respectively. Mice were sacrificed after 1, 3, 6, 9, and 48 hours and tissues were analysed for neutrophil and cytokine contents. In order to study the TLR4 signalling pathway of HS in the pancreas, genetically engineered mice lacking TLR4, Myeloid Differentiation primary response gene (88) (MyD88) or Interferon Regulatory Factor 3 (IRF3) were subjected to pancreatic infusion of HS. Results: Neutrophil sequestration and corresponding myeloperoxidase (MPO) activity in the pancreas were increased 9 hours following HS challenge. In wild-type mice, the monocyte chemoattractant protein-1(MCP-1) increased at 3 hours after infusion, while RANTES increased after 9 hours. TLR4, MyD88, and IRF3 knockout mice showed an abrogated neutrophil recruitment and myeloperoxidase activity in the HS group, while the LPS response was only abolished in TLR4 and MyD88 knockouts. Conclusions: The results of this study show that HS is capable of initiating a TLR4-dependent innate immune response in the pancreas which is distinctly different from that induced by LPS. This inflammatory response was mediated predominantly through IRF3-dependent pathway. Release of HS into the pancreatic duct may be one important mediator in the pancreatic ductal defence.
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| 4. |
- Andersson, Ellen, et al.
(författare)
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Tissue factor in predicted severe acute pancreatitis.
- 2010
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327. ; 16:48, s. 6128-6134
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Tidskriftsartikel (refereegranskat)abstract
- To study tissue factor (TF) in acute pancreatitis and evaluate the role of TF as a predictive marker of severity.
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| 5. |
- Andersson, Ellen, et al.
(författare)
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Treatment with anti-factor VIIa in acute pancreatitis in rats: Blocking both coagulation and inflammation?
- 2007
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 42:6, s. 765-770
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Acute pancreatitis starts as an autodigestive process restricted to the pancreas and progresses to a systemic inflammation via cytokine release into the blood stream. Several inhibitors of the coagulation cascade, including active- siteinactivated factor VIIa, have shown anti- inflammatory properties in other inflammatory models than acute pancreatitis. Free radical scavengers have proven useful in reducing the oxidative damage during hyperinflammatory conditions. The aim of this study was to investigate whether pretreatment with FVIIai would have any effect on the multiple organ dysfunction syndrome ( MODS) in severe acute pancreatitis. Material and methods. Experimental acute pancreatitis was induced by intraductal infusion of taurodeoxycholate in the pancreatic duct. The animals were pretreated with N- acetyl- cysteine and active- site- inactivated factor VIIa. Neutrophil infiltration in the lungs, ileum and colon was quantified by myeloperoxidase activity. Inflammatory markers, IL- 6 and MIP- 2, were measured using ELISA. Results. Tissue infiltration of neutrophils in the lungs, ileum and colon significantly increased during acute pancreatitis as compared to sham operation. These levels were reduced by pretreatment with N- acetylcysteine and active- site- inactivated factor VIIa. Levels of interleukin- 6 and macrophage inflammatory protein- 2 increased significantly during acute pancreatitis. Pretreatment with NAC and FVIIai reduced these levels. Conclusions. Both N- acetylcysteine and active- site- inactivated factor VIIa showed powerful antiinflammatory properties in experimental acute pancreatitis. As they exert their effects through different physiological mechanisms, they represent potential candidates for future multimodal treatment of acute pancreatitis.
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| 6. |
- Andersson, Roland, et al.
(författare)
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Acute pancreatitis - from cellular signalling to complicated clinical course.
- 2007
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Ingår i: HPB. - : Elsevier BV. - 1477-2574 .- 1365-182X. ; 9:6, s. 414-420
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Tidskriftsartikel (refereegranskat)abstract
- Acute pancreatitis (AP) is a common disease that has a mild to moderate course in most cases. During the last decade, a change in diagnostic facilities as well as improved intensive care have influenced both morbidity and mortality in AP. Still, however, a number of controversies and unresolved questions remain regarding AP. These include prognostic factors and how these may be used to improve outcome, diagnostic possibilities, their indications and optimal timing, and the systemic inflammatory reaction (systemic inflammatory response syndrome - SIRS) and its effect on the concomitant course of the disease and potential development of organ failure. The role of the gut has been suggested to be important in severe AP, but has recently been somewhat questioned. Despite extensive research, pharmacological and medical intervention of proven clinical value is scarce. Various aspects on surgical interventions, including endoscopic sphincterotomy, cholecystectomy and necrosectomy, as regards indications and timing, will be reviewed. Last, but not least, are the management of late complications and long-term outcome for patients with especially severe AP.
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| 7. |
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| 8. |
- Andersson, Roland, et al.
(författare)
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Gut barrier failure in critical illness: lessons learned from acute pancreatitis
- 2006
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Ingår i: Journal of Organ Dysfuntion. - : Informa UK Limited. - 1747-1060 .- 1747-1079. ; 2:2, s. 93-100
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Tidskriftsartikel (refereegranskat)abstract
- Gut barrier function is essential in critical illness and contributes to the systemic inflammatory response. Failure of the gut barrier includes both changes in microbial ecology, permeability and potential translocation, as well as local gut inflammatory response. The present review summarizes experiences made from acute pancreatitis, including pathophysiological mechanisms and ways of intervention.
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| 9. |
- Axelsson, Jakob B, et al.
(författare)
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Initiation of acute pancreatitis by heparan sulphate in the rat.
- 2008
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 43:4, s. 480-489
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The initiating events in the onset of pancreatitis are poorly understood. Possible candidates may be endogenous ligands, acting on receptors within ductal, acinar or stellate cells, which have previously been shown to cause a systemic inflammatory response syndrome. The aim of this study was to investigate whether acute pancreatitis could be induced by heparan sulphate (HS)infused into the pancreatic ducts in the rat. MATERIAL AND METHODS: Retrograde biliary-pancreatic infusion of heparan sulphate of different structures, taurodeoxycholate (TDC) or phosphate buffered saline (PBS) was performed. Local pancreatic inflammation was evaluated after 6 h by means of morphological evaluation, neutrophil and macrophage infiltration and levels of plasma amylase. Systemic inflammation was evaluated by measuring plasma IL-6, MCP-1 and CINC-1 concentrations. RESULTS: Heparan sulphate induced a local inflammatory response visualized as a rapid infiltration of neutrophils and macrophages into the pancreas. Heparan sulphate induced inflammation and oedema without causing damage to acinar cells, as measured by morphological changes and plasma amylase concentrations. Furthermore, an increase in serum concentrations of CINC-1 and IL-6 was seen. The positive control (TDC) had increased levels of all variables analysed and the negative control (heparan sulphate administered intraperitoneally) was without effects. CONCLUSIONS: Our findings suggest a receptor-mediated innate immune response of the pancreatic cells induced by heparan sulphate. This finding may be helpful in elucidating some of the mechanisms involved during the initiation of pancreatitis, as well as in the search for a potential future therapeutic application.
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| 10. |
- Axelsson, Jakob B
(författare)
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INITIATION OF EXPERIMENTAL ACUTE PANCREATITIS AND MODULATION OF INFLAMMATORY RESPONSE
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Heparan sulfate (HS), a substance common in the extracellular matrix on epithelial cells is present in the pancreas, lining the duct lumen. During pathological conditions, we propose that it can be shed from the ECM and bind to receptors on the cell surface, thus triggering an inflammatory response, which if excessive can cause acute pancreatitis (AP). Infusion of HS in the pancreatic duct in rats results in an inflammatory response without cellular damage, in similarity with lipopolysaccharide (LPS) infusion. The response differs though between the HS- and LPS-infusion both in regards to expressed chemokines and infiltrating cell types. HS-infusion predominantly causes early expression of CCL2 [monocyte chemoattractant protein-1 (MCP-1)] and subsequent early influx of monocytes. Increased expression of CXCL [cytokine-induced neutrophil chemoattractant-1 (CINC-1)] was not seen and neutrophils were shown to appear in the tissue later during the process. LPS, on the other hand, caused a rapid increase of CXCL (CINC-1) and also in early influx of neutrophils, in addition to similar patterns as HS-infusion of CCL2 (MCP-1) and monocytes. Taken together, the results indicate a receptor mediated innate immune response. Both HS and LPS has been shown to signal via the same receptor. We therefore suggest a difference in signaling pathways induced by the two ligands. Furthermore, the AP-induced systemic inflammation was studied. The anti-coagulant active site-inhibited factor VII (fVIIai) was shown to drastically decrease the inflammatory response. The effects in reducing neutrophil infiltration differed substantially between different organs. Nuclear factor kappa B (NFκB) activation was also shown to be affected by fVIIai. Pronounced differences between treatment effects was noted both depending on the studied organ and time point chosen. In conclusion a novel concept of the initiation of pancreatitis has been studied. The ducal epithelial cells are capable of signaling as a response to HS and LPS and to recruit inflammatory cells. This shows the importance of ductal cells and as a basis of new future pancreatitis specific interventions.
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