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


METHODS
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.


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
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.
Department of Clinical Sciences, Malmö, Section of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
Darbaz
D
Awla
Aree
A
Abdulla
Su
S
Zhang
Jonas
J
Roller
Michael D
MD
Menger
Sara
S
Regnér
Henrik
H
Thorlacius
D000208:Acute Disease; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D013656:Taurocholic Acid
D018925:Chemokines; D016169:Lymphocyte Function-Associated Antigen-1; D013656:Taurocholic Acid
Pancreas. 1996 Mar;12(2):183-8
8720667
J Clin Invest. 1997 Mar 15;99(6):1340-50
9077544
J Hepatol. 2006 Jun;44(6):1132-40
16466827
Br J Haematol. 2000 Aug;110(2):424-9
10971402
World J Gastroenterol. 2009 Mar 28;15(12):1427-30
19322914
Lab Invest. 2003 Apr;83(4):471-8
12695550
J Leukoc Biol. 1991 Mar;49(3):253-7
1671788
J Immunol. 1999 Mar 1;162(5):2511-20
10072490
Shock. 2008 Sep;30(3):254-9
18197144
Naunyn Schmiedebergs Arch Pharmacol. 2000 Aug;362(2):190-6
10961383
J Immunol. 1999 Nov 1;163(9):5029-38
10528208
J Biol Chem. 2008 Jul 25;283(30):20703-12
18511423
Ann Surg. 2002 Dec;236(6):777-84; discussion 784
12454516
Alcohol Clin Exp Res. 1998 May;22(S3 Pt 1):129S-132S
9622389
Blood. 2002 Jan 1;99(1):336-41
11756189
Hepatobiliary Pancreat Dis Int. 2009 Aug;8(4):351-7
19666402
Regul Pept. 2007 Jan 10;138(1):40-8
17014919
Br J Pharmacol. 2003 Sep;140(2):395-401
12970101
Cytokine Growth Factor Rev. 1998 Jun;9(2):167-73
9754710
Gastroenterology. 2002 Apr;122(4):974-84
11910350
Free Radic Biol Med. 2003 May 1;34(9):1115-6
12706491
J Immunol. 1995 Jun 15;154(12):6533-40
7759886
Gut. 2009 Nov;58(11):1508-16
19460768
Hepatology. 1996 Oct;24(4):888-94
8855193
World J Gastroenterol. 2006 Aug 21;12(31):5005-9
16937496
Gut. 1998 Sep;43(3):408-13
9863488
Mol Biol Evol. 2003 Nov;20(11):1767-77
12832630
Mediators Inflamm. 2009;2009:183760
20150959
J Exp Med. 1996 Apr 1;183(4):1415-26
8666900
Pancreatology. 2008;8(6):600-7
18849642
J Immunol. 1994 Oct 15;153(8):3724-33
7930589
J Leukoc Biol. 2002 Dec;72(6):1122-32
12488493
Immunology. 1992 Aug;76(4):655-61
1398754
Gastroenterology. 1999 Mar;116(3):694-701
10029629
Biochem Biophys Res Commun. 1994 Sep 15;203(2):1043-9
7522440
Br J Pharmacol. 2004 Feb;141(4):709-16
14744817
Am J Physiol Gastrointest Liver Physiol. 2007 May;292(5):G1396-402
17255363
N Engl J Med. 1989 Feb 9;320(6):365-76
2536474
J Immunol. 2002 Dec 15;169(12):7087-96
12471145
Cell. 1991 Dec 20;67(6):1033-6
1760836
Chin Med J (Engl). 2007 Oct 20;120(20):1757-61
18028766
Blood. 2000 Feb 1;95(3):911-20
10648403
Pancreas. 2008 Oct;37(3):288-94
18815551
J Clin Invest. 1999 Jan;103(2):261-9
9916138
JOP. 2001 Mar;2(2):69-77
11867866
Free Radic Biol Med. 2003 Oct 1;35(7):782-9
14583342
Ann Surg. 1992 Jan;215(1):44-56
1731649
Am J Pathol. 2005 Mar;166(3):945-52
15743805
Surgery. 2008 Sep;144(3):385-93
18707037