Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis.
Awla, Darbaz LU ; Abdulla, Aree LU ; Syk, Ingvar LU ; Jeppsson, Bengt LU ; Regnér, Sara LU
and Thorlacius, Henrik
LU
(2012)
In Journal of Leukocyte Biology
91.
p.711-719
- Abstract
- MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas.... (More)
- MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas. Treatment with the broad-spectrum inhibitor of MMPs, BB-94, markedly reduced activation of trypsinogen, levels of CXCL2, infiltration of neutrophils, and tissue damage in AP. Taurocholate challenge increased serum levels of MMP-9 but not MMP-2. Taurocholate-induced amylase levels, neutrophil accumulation, production of CXCL2, trypsinogen activation, and tissue damage in the pancreas were abolished in MMP-9-deficient mice. Moreover, secretions from activated neutrophils isolated from WT but not from MMP-9-deficient animals stimulated trypsinogen activation in acinar cells. Notably, rMMP-9 greatly enhanced activation of trypsinogen in acinar cells. These findings demonstrate that neutrophil-derived MMP-9 is a potent activator of trypsinogen in acinar cells and regulates pathological inflammation and tissue damage in AP. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2220586
- author
- Awla, Darbaz
LU
; Abdulla, Aree
LU
; Syk, Ingvar
LU
; Jeppsson, Bengt
LU
; Regnér, Sara
LU
and Thorlacius, Henrik
LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Leukocyte Biology
- volume
- 91
- pages
- 711 - 719
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- wos:000303837200006
- pmid:22100390
- scopus:84860912536
- pmid:22100390
- ISSN
- 1938-3673
- DOI
- 10.1189/jlb.0811443
- language
- English
- LU publication?
- yes
- id
- 7fd42218-bd0c-4309-8dae-9e4e7dec9c3b (old id 2220586)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/22100390?dopt=Abstract
- date added to LUP
- 2016-04-04 07:18:18
- date last changed
- 2022-01-29 02:00:27
@article{7fd42218-bd0c-4309-8dae-9e4e7dec9c3b,
abstract = {{MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas. Treatment with the broad-spectrum inhibitor of MMPs, BB-94, markedly reduced activation of trypsinogen, levels of CXCL2, infiltration of neutrophils, and tissue damage in AP. Taurocholate challenge increased serum levels of MMP-9 but not MMP-2. Taurocholate-induced amylase levels, neutrophil accumulation, production of CXCL2, trypsinogen activation, and tissue damage in the pancreas were abolished in MMP-9-deficient mice. Moreover, secretions from activated neutrophils isolated from WT but not from MMP-9-deficient animals stimulated trypsinogen activation in acinar cells. Notably, rMMP-9 greatly enhanced activation of trypsinogen in acinar cells. These findings demonstrate that neutrophil-derived MMP-9 is a potent activator of trypsinogen in acinar cells and regulates pathological inflammation and tissue damage in AP.}},
author = {{Awla, Darbaz and Abdulla, Aree and Syk, Ingvar and Jeppsson, Bengt and Regnér, Sara and Thorlacius, Henrik}},
issn = {{1938-3673}},
language = {{eng}},
pages = {{711--719}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Journal of Leukocyte Biology}},
title = {{Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis.}},
url = {{http://dx.doi.org/10.1189/jlb.0811443}},
doi = {{10.1189/jlb.0811443}},
volume = {{91}},
year = {{2012}},
}