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

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 postcapillary 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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Awla D,Abdulla A,Zhang S,Roller J,Menger MD,Regnér S,Thorlacius H

doi

10.1111/j.1476-5381.2011.01225.x

subject

Has Abstract

pub_date

2011-05-01 00:00:00

pages

413-23

issue

eissn

0007-1188

issn

1476-5381

journal_volume

163

pub_type

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