Inhibition of Mac-1-dependent leukocyte adhesion by Y-24180, an anti-inflammatory agent, in mice

Y-24180 (4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine), an antagonist of platelet-activating factor (PAF), has been already clarified to suppress the expression of an adhesion molecule, Mac-1, on human neutrophils in the previous in vitro study. In the present paper, we examined the effect of Y-24180 on in vivo Mac-1 expression on mouse neutrophils using a lipopolysaccharide-induced leukocyte reduction model in which Mac-1-dependent infiltration of neutrophils was involved. Prophylactic oral administration of Y-24180 inhibited the induction of Mac-1-strongly positive neutrophils by intraperitoneal injection of lipopolysaccharide and prevented the reduction of leukocyte number. In contrast, WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-2-yl]-1-(4-morpholinyl)-1-propanone), another PAF antagonist, showed little effect. PAF injection failed to induce the Mac-1-strongly positive neutrophils in peripheral blood and the reduction of circulating leukocytes, indicating that PAF was not concerned with the lipopolysaccharide-induced up-regulation of Mac-1 expression and leukocyte reduction. Y-24180 inhibited the leukocyte infiltration also in the thioglycollate medium-induced peritonitis, which was mediated by Mac-1-dependent leukocyte adhesion. These results indicate that Y-24180 inhibits the leukocyte infiltration into the inflamed sites by suppressing Mac-1 expression on leukocytes in vivo and can contribute to the improvement of inflammatory diseases in which the Mac-1-dependent leukocyte adhesion is involved.