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.

• Authors: Darbaz Awla, Aree Abdulla, Su Zhang, Jonas Roller, Michael D Menger, Sara Regnér, Henrik Thorlacius
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 163 Issue 2 Pg. 413-23 (May 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21244370 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Chemokines
• Lymphocyte Function-Associated Antigen-1
• Taurocholic Acid

Topics

• Acute Disease
• Animals
• Chemokines (metabolism)
• Lymphocyte Function-Associated Antigen-1 (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neutrophil Infiltration
• Pancreas (immunology, metabolism, pathology)
• Pancreatitis (chemically induced, immunology, pathology)
• Taurocholic Acid