Acute pancreatitis, from local defense to remote organ injury
(2013) In Lund University Faculty of Medicine Doctoral Dissertation Series 2013:23.- Abstract
- Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Acute abdominal pain is the most common symptom. Pancreatic injury is mild in 80% of patients, who recover without complications. The remaining patients have a severe disease with local and systemic complications such as acute lung injury (ALI). Gallstone migration into the common bile duct and alcohol abuse are the most frequent causes of pancreatitis in adults.
Heparan sulfate (HS) is a common component of extracellular matrix which lines the ductal cells in the pancreas. During the process of the disease, active enzymes in the pancreas will cause shedding of HS.
We have shown that HS is able to start an inflammatory response in the pancreas. This... (More) - Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Acute abdominal pain is the most common symptom. Pancreatic injury is mild in 80% of patients, who recover without complications. The remaining patients have a severe disease with local and systemic complications such as acute lung injury (ALI). Gallstone migration into the common bile duct and alcohol abuse are the most frequent causes of pancreatitis in adults.
Heparan sulfate (HS) is a common component of extracellular matrix which lines the ductal cells in the pancreas. During the process of the disease, active enzymes in the pancreas will cause shedding of HS.
We have shown that HS is able to start an inflammatory response in the pancreas. This response was mediated via Toll like receptor-4 and involved both MyD88-dependent and –independent pathways. We propose that HS has a role in the monitoring of pancreatic tissue well-being.
Acute lung injury is the most common extra-pancreatic complication in the acute pancreatitis. Macrophages are a heterogeneous population based on their anatomical location and their micro-environment. Our data showed an enriched population of CD68+F4/80- macrophages in the lungs of animals with AP. This population had an increased expression of CD206 (a cell marker of alternatively activated macrophages) and CCR2 (the receptor for CCL2, an important chemoattractant for macrophages). Studying lung macrophages for different phenotypic markers, their polarization, activation and recruitment, in the context of acute lung injury, is a novel area to potentially identify interventions which may improve the outcome of acute lung injury.
Macrophages are a source of various remodeling cytokines including TGF-β.
TGF-β not only participates in the late phase of acute lung injury, but also might be active early in acute lung injury and potentially could contribute to the development of pulmonary edema.
Our data showed an increase in the level of TGF-β1 in the lungs of the acute pancreatitis group early on but this was in parallel with an increase in the level of inhibitory Smad7. The level of Smad7 was back to the control level after 24 h when there was an increase in the nuclear translocation of phosphorylated Smad2. Our findings suggest that TGF-β signaling pathway can be activated in the early phase of ALI due to AP and may have a contributing role in the pathogenesis of lung injury. Therefore, TGF-β signaling pathway can represent a potential strategy to be used in the future treatment of ALI. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3512903
- author
- Akbarshahi, Hamid LU
- supervisor
- opponent
-
- Chambers, Rachel, Centre for inflammation and tissue repair, University College London
- organization
- publishing date
- 2013
- type
- Thesis
- publication status
- published
- subject
- keywords
- Acute pancreatitis, heparan sulfate, damage associated molecular patterns, toll-like receptor4, MyD88, IRF-3, acute lung injury, macrophages, transforming growth factor-beta, Smad
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- volume
- 2013:23
- pages
- 61 pages
- publisher
- Surgery (Lund)
- defense location
- Belfrage lecture hall, BMC D15, Lund
- defense date
- 2013-03-08 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-87189-92-0
- language
- English
- LU publication?
- yes
- id
- ef7af9b1-49f9-429c-ba1b-db8717a0bd16 (old id 3512903)
- date added to LUP
- 2016-04-01 14:08:36
- date last changed
- 2019-05-22 00:28:40
@phdthesis{ef7af9b1-49f9-429c-ba1b-db8717a0bd16,
abstract = {{Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Acute abdominal pain is the most common symptom. Pancreatic injury is mild in 80% of patients, who recover without complications. The remaining patients have a severe disease with local and systemic complications such as acute lung injury (ALI). Gallstone migration into the common bile duct and alcohol abuse are the most frequent causes of pancreatitis in adults. <br/><br>
Heparan sulfate (HS) is a common component of extracellular matrix which lines the ductal cells in the pancreas. During the process of the disease, active enzymes in the pancreas will cause shedding of HS. <br/><br>
We have shown that HS is able to start an inflammatory response in the pancreas. This response was mediated via Toll like receptor-4 and involved both MyD88-dependent and –independent pathways. We propose that HS has a role in the monitoring of pancreatic tissue well-being.<br/><br>
Acute lung injury is the most common extra-pancreatic complication in the acute pancreatitis. Macrophages are a heterogeneous population based on their anatomical location and their micro-environment. Our data showed an enriched population of CD68+F4/80- macrophages in the lungs of animals with AP. This population had an increased expression of CD206 (a cell marker of alternatively activated macrophages) and CCR2 (the receptor for CCL2, an important chemoattractant for macrophages). Studying lung macrophages for different phenotypic markers, their polarization, activation and recruitment, in the context of acute lung injury, is a novel area to potentially identify interventions which may improve the outcome of acute lung injury.<br/><br>
Macrophages are a source of various remodeling cytokines including TGF-β.<br/><br>
TGF-β not only participates in the late phase of acute lung injury, but also might be active early in acute lung injury and potentially could contribute to the development of pulmonary edema.<br/><br>
Our data showed an increase in the level of TGF-β1 in the lungs of the acute pancreatitis group early on but this was in parallel with an increase in the level of inhibitory Smad7. The level of Smad7 was back to the control level after 24 h when there was an increase in the nuclear translocation of phosphorylated Smad2. Our findings suggest that TGF-β signaling pathway can be activated in the early phase of ALI due to AP and may have a contributing role in the pathogenesis of lung injury. Therefore, TGF-β signaling pathway can represent a potential strategy to be used in the future treatment of ALI.}},
author = {{Akbarshahi, Hamid}},
isbn = {{978-91-87189-92-0}},
issn = {{1652-8220}},
keywords = {{Acute pancreatitis; heparan sulfate; damage associated molecular patterns; toll-like receptor4; MyD88; IRF-3; acute lung injury; macrophages; transforming growth factor-beta; Smad}},
language = {{eng}},
publisher = {{Surgery (Lund)}},
school = {{Lund University}},
series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
title = {{Acute pancreatitis, from local defense to remote organ injury}},
url = {{https://lup.lub.lu.se/search/files/3813303/3514627.pdf}},
volume = {{2013:23}},
year = {{2013}},
}