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Trypsinogen and neutrophil activation in acute Pancreatitis

Hartman Magnusson, Hannes LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:7.
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... (More)
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. (Less)
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author
supervisor
opponent
  • Laukkarinen, Johanna, University of Tampere, Department of Gastroenterology and Alimentary Tract Surgery, Finland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Acute pancreatitis, trypsinogen activation, adhesion, neutrophil extracellular traps
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:7
pages
83 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Kvinnoklinikens aula, Jan Waldenströms gata 47, plan 3, Skånes universitetssjukhus i Malmö.
defense date
2015-01-29 13:00
ISSN
1652-8220
ISBN
978-91-7619-087-6
language
English
LU publication?
yes
id
d790b9a6-4f9b-4fbd-8f3f-4bd3242074ff (old id 4925564)
date added to LUP
2015-01-08 11:41:23
date last changed
2016-09-19 08:44:51
@phdthesis{d790b9a6-4f9b-4fbd-8f3f-4bd3242074ff,
  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.<br/><br>
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<br/><br>
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<br/><br>
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. <br/><br>
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.},
  author       = {Hartman Magnusson, Hannes},
  isbn         = {978-91-7619-087-6},
  issn         = {1652-8220},
  keyword      = {Acute pancreatitis,trypsinogen activation,adhesion,neutrophil extracellular traps},
  language     = {eng},
  pages        = {83},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Trypsinogen and neutrophil activation in acute Pancreatitis},
  volume       = {2015:7},
  year         = {2015},
}