The carbohydrate sialyl Lewis(x) (sLe(x)) sulfated glycomimetic GM2941 attenuates glucan-induced pulmonary granulomatous vasculitis in the rat

We examined the protective effects of GM2941, a sulfated glycomimetic of the complex carbohydrate sialyl Lewis(x), in a model of pulmonary granuloma development. This study was based on the rationale that formation of glucan- induced lung granulomas is dependent on neutrophils and that sialyl Lewis(x) glycomimetic (GM2941)interferes, in vitro, with P-selectin-dependent neutrophil-endothelial adhesive interactions. Infusion of particulate yeast cell wall glucan into rats results in the rapid (48 hr) formation of monocyte/macrophage-rich angiocentric pulmonary granulomas. Development of granulomas exhibits a temporal pattern characterized by the early, transient influx of neutrophils into blood vessel walls at sites of glucan embolization, followed by accumulation of monocytes and macrophages that constitute the definitive angiocentric lesions. Within 1 hr after the infusion of glucan, immunohistochemical analysis revealed up-regulation of blood vessel wall-associated P-selectin. Previous studies utilizing neutrophil-depleted animals have revealed that neutrophils, although not present in definitive lesions, are required for full granuloma development. The potential of GM2941 to inhibit neutrophil-endothelial cell adhesive interactions was demonstrated by the ability of the compound to inhibit P- selectin-mediated adhesion to histamine-stimulated HUVECs. Infusion of GM2941 retarded pulmonary granuloma development in a dose-dependent manner. Whole- lung myeloperoxidase activity, measured at the time of peak neutrophil accumulation, was significantly reduced in animals pretreated with GM2941 (30 mg/kg, 24 μM/kg), which suggests that this compound affords protection, at least in part, through impedance of neutrophil recruitment. These data indicate that GM2941 affords a significant degree of protection against granuloma formation associated with glucan infusion, probably through the interruption of neutrophil recruitment.