Adhesion molecule expression in postischemic microvascular dysfunction: Activity of a micronized purified flavonoid fraction

Ischemia and reperfusion (I/R) induces neutrophil infiltration in skeletal muscle that is localized to the ischemic region. To transmigrate at ischemi c regions, granulocytes must first arrest in the postcapillary venular segm ent of the microcirculation. Initially, leukocytes roll along the endotheli um of these venules, a weak adhesive interaction that is mediated by the se lectins (L-, E-, and P-selectin). Leukocyte rolling functions to slow the n eutrophil during its transit through the microcirculation, thereby allowing it to monitor its local environment for the presence of activating factors arising from the ischemic tissues. When activated, the rolling granulocyte is rendered capable of forming the stronger adhesive interactions that all ow the cell to become arrested in postcapillary venules in the ischemic reg ion. These adhesive interactions are mediated by a leukocyte glycoprotein c omplex designated CD11/CD18 and intercellular adhesion molecule-1 (ICAM-1) expressed on endothelial cells. The stationary neutrophil uses the gradient in concentration of soluble chemoattractants liberated from ischemic tissu es as a directional cue to move from the vascular to extravascular compartm ent, being guided in its transit across the endothelium by interactions wit h platelet endothelial cell adhesion molecule-1 (PECAM-1), an adhesive mole cule localized to the interendothelial cleft. This paper reviews current un derstanding of the mechanisms underlying the establishment of leukocyte/ en dothelial cell interactions in postischemic skeletal muscle in terms of spe cific adhesion molecules that participate in neutrophil sequestration after I/R. Discovery of the molecular determinants of neutrophil/endothelial cel l adhesion has uncovered potential mechanisms whereby agents exhibiting ant i-adhesive properties may act. The micronized purified flavonoid fraction ( 450 mg diosmin, 50 mg hesperidin) prevents I/R-induced leukocyte adhesion i n skeletal muscle. This anti-adhesive effect appears to be mediated at leas t in part by inhibition of induced expression of ICAM-1.