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Lymphocyte function antigen‐1 regulates neutrophil recruitment and tissue damage in acute pancreatitis
Author(s) -
Awla Darbaz,
Abdulla Aree,
Zhang Su,
Roller Jonas,
Menger Michael D,
Regnér Sara,
Thorlacius Henrik
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01225.x
Subject(s) - pancreas , cxcl2 , chemokine , acute pancreatitis , trypsinogen , inflammation , endothelium , lymphocyte function associated antigen 1 , pancreatitis , infiltration (hvac) , medicine , pathology , immunology , biology , endocrinology , intercellular adhesion molecule 1 , trypsin , biochemistry , physics , chemokine receptor , enzyme , thermodynamics
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.