Trypsinogen and neutrophil activation in acute Pancreatitis
Author
Summary, in English
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.
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.
Department/s
Publishing year
2015
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2015:7
Full text
Document type
Dissertation
Publisher
Department of Clinical Sciences, Lund University
Topic
- Surgery
Keywords
- Acute pancreatitis
- trypsinogen activation
- adhesion
- neutrophil extracellular traps
Status
Published
Research group
- Surgery
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-087-6
Defence date
29 January 2015
Defence time
13:00
Defence place
Kvinnoklinikens aula, Jan Waldenströms gata 47, plan 3, Skånes universitetssjukhus i Malmö.
Opponent
- Johanna Laukkarinen