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INITIATION OF EXPERIMENTAL ACUTE PANCREATITIS AND MODULATION OF INFLAMMATORY RESPONSE

Axelsson, Jakob B LU (2008) In Lund University Faculty of Medicine Doctoral Dissertation Series 2008:31.
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... (More)
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. (Less)
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author
supervisor
opponent
  • Hammarqvist, Folke, Karolinska Institutet, Stockholm
organization
publishing date
type
Thesis
publication status
published
subject
keywords
nuclear factor kappa B, neutrophils, monocytes, acute pancreatitis, ductal cells, active site-inhibited factor seven, heparan sulfate, lipopolysaccharide, innate immune response
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2008:31
pages
121 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Belfragesalen, D15, Biomedicinskt Centrum (BMC), Lund
defense date
2008-04-04 13:00
ISSN
1652-8220
ISBN
978-91-85897-84-1
language
English
LU publication?
yes
id
05492f47-288b-4ba7-90d6-a07348e27bc5 (old id 1047686)
date added to LUP
2008-03-14 13:38:24
date last changed
2016-09-19 08:44:48
@phdthesis{05492f47-288b-4ba7-90d6-a07348e27bc5,
  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).<br/><br>
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.<br/><br>
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.<br/><br>
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.<br/><br>
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.},
  author       = {Axelsson, Jakob B},
  isbn         = {978-91-85897-84-1},
  issn         = {1652-8220},
  keyword      = {nuclear factor kappa B,neutrophils,monocytes,acute pancreatitis,ductal cells,active site-inhibited factor seven,heparan sulfate,lipopolysaccharide,innate immune response},
  language     = {eng},
  pages        = {121},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {INITIATION OF EXPERIMENTAL ACUTE PANCREATITIS AND MODULATION OF INFLAMMATORY RESPONSE},
  volume       = {2008:31},
  year         = {2008},
}