A statin-based inhibitor of lymphocyte function antigen-1 protects against ischemia/reperfusion-induced leukocyte adhesion in the colon.
1. Statins are mainly used to control hypercholesterolemia; however, recent studies have also ascribed anti-inflammatory effects to the statins. LFA703 is a novel statin-derived compound, which potently inhibits lymphocyte function antigen-1 (LFA-1, CD11a/CD18) but does not affect HMG-CoA reductase activity. 2. The objective of this study was to examine the anti-inflammatory mechanisms of LFA703 in ischemia/reperfusion (I/R)-induced leukocyte-endothelium interactions in the colon. For this purpose, the superior mesenteric artery was occluded for 30 min and leukocyte responses were analyzed in colonic venules after 120 min of reperfusion in mice using inverted intravital fluorescence microscopy. 3. First, the inhibitory mechanisms of LFA703 on leukocyte adhesion were investigated in vitro using a mouse CD4+8+ thymocyte cell line. Immunoneutralization of LFA-1 and ICAM-1 abolished leukocyte adhesion, whereas inhibition of VLA-4 had no effect in this in vitro assay. Indeed, it was found that LFA703 dose-dependently reduced LFA-1-dependent leukocyte adhesion to mouse endothelial cells in vitro with an IC50 of 3.2 microm. 4. I/R caused an increase in leukocyte rolling and adhesion in colonic venules. Immunoneutralization of LFA-1 significantly reduced I/R-induced leukocyte adhesion by 89% in colonic venules. In contrast, I/R-provoked leukocyte rolling was insensitive to inhibition of LFA-1 function. 5. Administration of 30 mg kg-1 of LFA703 decreased reperfusion-induced leukocyte adhesion by more than 91%, while the level of leukocyte rolling was unchanged, suggesting that LFA703 effectively blocked LFA-1-dependent firm adhesion of leukocyte in the colon. However, LFA703 did not decrease the expression of LFA-1 on circulating leukocytes. 6. This study demonstrates that LFA-1 is indeed a critical adhesion molecule in mediating postischemic leukocyte adhesion in the colon. Moreover, this is the first study showing that a statin-based synthetic compound has the capacity to abolish LFA-1-dependent leukocyte adhesion in I/R. These novel findings may have great implications in the clinical treatment of conditions associated with I/R-induced tissue injury, such as organ transplantation, trauma and major surgery.
Wan
Min Xiu
MX
Department of Surgery, Malmö University Hospital, Lund University, Malmö S- 205 02, Sweden.
Schramm
Rene
R
Klintman
Daniel
D
Welzenbach
Karl
K
Weitz-Schmidt
Gabriele
G
Thorlacius
Henrik
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D003106:Colon / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D007958:Leukocyte Count; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000503:physiopathology*
D000911:Antibodies, Monoclonal; C430123:LFA703; D016169:Lymphocyte Function-Associated Antigen-1; D009281:Naphthalenes