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Lymphocyte function antigen-1 regulates neutrophil recruitment and tissue damage in acute pancreatitis.

Awla, Darbaz LU ; Abdulla, Aree LU ; Zhang, Su LU ; Roller, Jonas; Menger, Michael; Regnér, Sara LU and Thorlacius, Henrik LU (2011) In British Journal of Pharmacology 163. p.413-423
Abstract
Background and purpose: Leucocyte infiltration is a rate-limiting step in the pathophysiology of acute pancreatitis (AP) although the adhesive mechanisms supporting leucocyte-endothelium interactions in the pancreas remain elusive. The aim of this study was to define the role of lymphocyte function antigen-1 (LFA-1) in regulating neutrophil-endothelium interactions and tissue damage in severe AP. Experimental approach: Pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in mice. LFA-1 gene-targeted mice and an antibody directed against LFA-1 were used to define the role of LFA-1. Key results: Taurocholate challenge caused a clear-cut increase in serum amylase, neutrophil infiltration, CXCL2... (More)
Background and purpose: Leucocyte infiltration is a rate-limiting step in the pathophysiology of acute pancreatitis (AP) although the adhesive mechanisms supporting leucocyte-endothelium interactions in the pancreas remain elusive. The aim of this study was to define the role of lymphocyte function antigen-1 (LFA-1) in regulating neutrophil-endothelium interactions and tissue damage in severe AP. Experimental approach: Pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in mice. LFA-1 gene-targeted mice and an antibody directed against LFA-1 were used to define the role of LFA-1. Key results: Taurocholate challenge caused a clear-cut increase in serum amylase, neutrophil infiltration, CXCL2 (macrophage inflammatory protein-2) formation, trypsinogen activation and tissue damage in the pancreas. Inhibition of LFA-1 function markedly reduced taurocholate-induced amylase levels, accumulation of neutrophils, production of CXC chemokines and tissue damage in the pancreas. Notably, intravital microscopy revealed that inhibition of LFA-1 abolished taurocholate-induced leucocyte adhesion in postcapillray venules of the pancreas. In addition, pulmonary infiltration of neutrophils was attenuated by inhibition of LFA-1 in mice challenged with taurocholate. However, interference with LFA-1 had no effect on taurocholate-induced activation of trypsinogen in the pancreas. Conclusions and Implications: Our novel data suggest that LFA-1 plays a key role in regulating neutrophil recruitment, CXCL2 formation and tissue injury in the pancreas. Moreover, these results suggest that LFA-1-mediated inflammation is a downstream component of trypsinogen activation in the pathophysiology of AP. Thus, we conclude that targeting LFA-1 may be a useful approach to protect against pathological inflammation in the pancreas. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
British Journal of Pharmacology
volume
163
pages
413 - 423
publisher
The British Pharmacological Society
external identifiers
  • WOS:000289642600018
  • PMID:21244370
  • Scopus:79954530675
ISSN
1476-5381
DOI
10.1111/j.1476-5381.2011.01225.x
language
English
LU publication?
yes
id
9d11cab5-aee4-4be1-bd92-3d098e6208ed (old id 1777347)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21244370?dopt=Abstract
date added to LUP
2011-02-01 14:43:52
date last changed
2016-11-06 04:27:08
@misc{9d11cab5-aee4-4be1-bd92-3d098e6208ed,
  abstract     = {Background and purpose: Leucocyte infiltration is a rate-limiting step in the pathophysiology of acute pancreatitis (AP) although the adhesive mechanisms supporting leucocyte-endothelium interactions in the pancreas remain elusive. The aim of this study was to define the role of lymphocyte function antigen-1 (LFA-1) in regulating neutrophil-endothelium interactions and tissue damage in severe AP. Experimental approach: Pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in mice. LFA-1 gene-targeted mice and an antibody directed against LFA-1 were used to define the role of LFA-1. Key results: Taurocholate challenge caused a clear-cut increase in serum amylase, neutrophil infiltration, CXCL2 (macrophage inflammatory protein-2) formation, trypsinogen activation and tissue damage in the pancreas. Inhibition of LFA-1 function markedly reduced taurocholate-induced amylase levels, accumulation of neutrophils, production of CXC chemokines and tissue damage in the pancreas. Notably, intravital microscopy revealed that inhibition of LFA-1 abolished taurocholate-induced leucocyte adhesion in postcapillray venules of the pancreas. In addition, pulmonary infiltration of neutrophils was attenuated by inhibition of LFA-1 in mice challenged with taurocholate. However, interference with LFA-1 had no effect on taurocholate-induced activation of trypsinogen in the pancreas. Conclusions and Implications: Our novel data suggest that LFA-1 plays a key role in regulating neutrophil recruitment, CXCL2 formation and tissue injury in the pancreas. Moreover, these results suggest that LFA-1-mediated inflammation is a downstream component of trypsinogen activation in the pathophysiology of AP. Thus, we conclude that targeting LFA-1 may be a useful approach to protect against pathological inflammation in the pancreas.},
  author       = {Awla, Darbaz and Abdulla, Aree and Zhang, Su and Roller, Jonas and Menger, Michael and Regnér, Sara and Thorlacius, Henrik},
  issn         = {1476-5381},
  language     = {eng},
  pages        = {413--423},
  publisher    = {ARRAY(0x8d88b58)},
  series       = {British Journal of Pharmacology},
  title        = {Lymphocyte function antigen-1 regulates neutrophil recruitment and tissue damage in acute pancreatitis.},
  url          = {http://dx.doi.org/10.1111/j.1476-5381.2011.01225.x},
  volume       = {163},
  year         = {2011},
}