Rho-kinase signalling regulates trypsinogen activation and tissue damage in severe acute pancreatitis.
Awla, Darbaz LU ; Hartman Magnusson, Hannes LU ; Abdulla, Aree LU ; Zhang, Songen LU ; Rahman, Milladur LU
; Regnér, Sara
LU
and Thorlacius, Henrik
LU
(2011)
In British Journal of Pharmacology
162.
p.648-658
- Abstract
- Background and purpose: Severe acute pancreatitis (SAP) is characterized by trypsinogen activation, infiltration of leucocytes and tissue necrosis but the intracellular signalling mechanisms regulating organ injury in the pancreas remain elusive. Rho-kinase is a potent regulator of specific cellular processes effecting several pro-inflammatory activities. Herein, we examined the role of Rho-kinase signalling in acute pancreatitis. Experimental approach: Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a Rho-kinase inhibitor Y-27632 (0.5-5 mg kg(-1) ) before induction of pancreatitis. Key results: Taurocholate infusion caused a clear-cut increase in serum amylase,... (More)
- Background and purpose: Severe acute pancreatitis (SAP) is characterized by trypsinogen activation, infiltration of leucocytes and tissue necrosis but the intracellular signalling mechanisms regulating organ injury in the pancreas remain elusive. Rho-kinase is a potent regulator of specific cellular processes effecting several pro-inflammatory activities. Herein, we examined the role of Rho-kinase signalling in acute pancreatitis. Experimental approach: Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a Rho-kinase inhibitor Y-27632 (0.5-5 mg kg(-1) ) before induction of pancreatitis. Key results: Taurocholate infusion caused a clear-cut increase in serum amylase, pancreatic neutrophil infiltration, acinar cell necrosis and oedema formation in the pancreas. Levels of pancreatic myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2), trypsinogen activation peptide (TAP) and lung MPO were significantly increased, indicating local and systemic disease. Inhibition of Rho-kinase activity dose-dependently protected against pancreatitis. For example, 5 mg kg(-1) Y-27632 reduced acinar cell necrosis, leucocyte infiltration and pancreatic oedema by 90%, 89% and 58% respectively as well as tissue levels of MPO by 75% and MIP-2 by 84%. Moreover, Rho-kinase inhibition decreased lung MPO by 75% and serum amylase by 83%. Pancreatitis-induced TAP levels were reduced by 61% in Y-27632-treated mice. Inhibition of Rho-kinase abolished secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. Conclusions and Implications: Our novel data suggest that Rho-kinase signalling plays an important role in acute pancreatitis by regulating trypsinogen activation and subsequent CXC chemokine formation, neutrophil infiltration and tissue injury. Thus, these results indicate that Rho-kinase may constitute a novel target in the management of SAP. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1711222
- author
- Awla, Darbaz
LU
; Hartman Magnusson, Hannes
LU
; Abdulla, Aree
LU
; Zhang, Songen
LU
; Rahman, Milladur
LU
; Regnér, Sara
LU
and Thorlacius, Henrik
LU
- organization
- publishing date
- 2011
- type
- Contribution to journal
- publication status
- published
- subject
- in
- British Journal of Pharmacology
- volume
- 162
- pages
- 648 - 658
- publisher
- Wiley
- external identifiers
-
- wos:000286055300009
- pmid:20942858
- scopus:78651467246
- pmid:20942858
- ISSN
- 1476-5381
- DOI
- 10.1111/j.1476-5381.2010.01060.x
- language
- English
- LU publication?
- yes
- id
- 2099b06f-26cd-445d-9373-98395346f840 (old id 1711222)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/20942858?dopt=Abstract
- date added to LUP
- 2016-04-04 09:31:46
- date last changed
- 2023-03-12 18:22:09
@article{2099b06f-26cd-445d-9373-98395346f840,
abstract = {{Background and purpose: Severe acute pancreatitis (SAP) is characterized by trypsinogen activation, infiltration of leucocytes and tissue necrosis but the intracellular signalling mechanisms regulating organ injury in the pancreas remain elusive. Rho-kinase is a potent regulator of specific cellular processes effecting several pro-inflammatory activities. Herein, we examined the role of Rho-kinase signalling in acute pancreatitis. Experimental approach: Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a Rho-kinase inhibitor Y-27632 (0.5-5 mg kg(-1) ) before induction of pancreatitis. Key results: Taurocholate infusion caused a clear-cut increase in serum amylase, pancreatic neutrophil infiltration, acinar cell necrosis and oedema formation in the pancreas. Levels of pancreatic myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2), trypsinogen activation peptide (TAP) and lung MPO were significantly increased, indicating local and systemic disease. Inhibition of Rho-kinase activity dose-dependently protected against pancreatitis. For example, 5 mg kg(-1) Y-27632 reduced acinar cell necrosis, leucocyte infiltration and pancreatic oedema by 90%, 89% and 58% respectively as well as tissue levels of MPO by 75% and MIP-2 by 84%. Moreover, Rho-kinase inhibition decreased lung MPO by 75% and serum amylase by 83%. Pancreatitis-induced TAP levels were reduced by 61% in Y-27632-treated mice. Inhibition of Rho-kinase abolished secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. Conclusions and Implications: Our novel data suggest that Rho-kinase signalling plays an important role in acute pancreatitis by regulating trypsinogen activation and subsequent CXC chemokine formation, neutrophil infiltration and tissue injury. Thus, these results indicate that Rho-kinase may constitute a novel target in the management of SAP.}},
author = {{Awla, Darbaz and Hartman Magnusson, Hannes and Abdulla, Aree and Zhang, Songen and Rahman, Milladur and Regnér, Sara and Thorlacius, Henrik}},
issn = {{1476-5381}},
language = {{eng}},
pages = {{648--658}},
publisher = {{Wiley}},
series = {{British Journal of Pharmacology}},
title = {{Rho-kinase signalling regulates trypsinogen activation and tissue damage in severe acute pancreatitis.}},
url = {{http://dx.doi.org/10.1111/j.1476-5381.2010.01060.x}},
doi = {{10.1111/j.1476-5381.2010.01060.x}},
volume = {{162}},
year = {{2011}},
}