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.