Lipoxin A(4) stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

Three different stable lipoxin A(4) (LXA(4)) analogs (i.e., 16-phenoxy-LXA(4)-Me, 15-cyclohexyl-LXA(4)-Me, and 15-R/S-methyl-LXA(4)-Me) were studied for their ability to modulate leukocyte endothelial cell interactions in the rat mesenteric microvasculature. Superfusion of the rat mesentery with 50 mu mol/liter N-G-nitro-L-arginine methyl ester (L-NAME) caused a significant, time-dependent increase in leukocyte rolling (56 +/- 8 cells/min; P < 0.01 vs, control) and leukocyte adherence (12.5 +/- 1.2 cells/100 mu m length of venule; P < 0.01 vs, control) after 120 min of superfusion, Concomitant superfusion of the rat mesentery with 10 nmol/liter of each of three lipoxin analogs consistently and markedly attenuated L-NAME-induced leukocyte rolling to 10 a 4 (P < 0.01), 4 +/- 1 (P < 0.01), and 32 +/- 7 (P < 0.05) cells/min, and adherence to 4 +/- 0.8 (P < 0.01), 1.1 +/- 0.4 (P < 0.01), and 7 +/- 0.7 (P < 0.05) cells/100 mu m length of venule (16-phenoxy-LXA(4)-Me, 15-cyclohexyl-LXA(4)-Me, and 15-R/S-methyl-LXA(4)-Me, respectively), No alterations of systemic blood pressure or mesenteric venular shear rates were observed in any group, Immunohistochemical up-regulation of P-selectin expression on intestinal venular endothelium was significantly increased (P < 0.01) after exposure to L-NAME, and this was significantly attenuated by these lipoxin analogs (P < 0.01), Thus, in vivo superfusion of the rat mesentery with stable lipoxin analogs at 10 nmol/liter reduces L-NAME-induced leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression, This anti-inflammatory mechanism may represent a novel and potent regulatory action of lipoxins on the immune system.