Abstract
We examined the protective effects of GM2941, a sulfated glycomimetic of the complex carbohydrate sialyl Lewisx, 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 Lewisx 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.
Footnotes
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Send reprint requests to: Jeffrey S. Warren, M.D., Department of Pathology, Box 0602, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109-0602.
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↵1 These studies were supported in part by the National Institutes of Health (HL 48287 and 5T 32-HL 07517).
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↵2 K.S.K. was supported in part by the American Heart Association of Michigan (21F956 Fellowship).
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↵3 M.B.A. is a senior research scientist in Medicinal Chemistry at Glycomed Incorporated (a fully owned subsidiary of Ligand Pharmaceuticals Incorporated) of Alameda, CA.
- Abbreviations:
- sLex
- sialyl Lewisx
- ARDS
- adult respiratory distress syndrome
- MCP-1
- monocyte chemoattractant protein-1
- ROIs
- reactive oxygen intermediates
- MPO
- myeloperoxidase
- HUVECs
- human umbilical vein endothelial cells
- BCECF-AM
- 2′,7′-bis-(2-carboxyethyl)-5(and 6)-carboxyfluorescein, acetoxymethyl
- WBC
- white blood cell
- ELISA
- enzyme-linked immunoabsorbant assay
- PBS
- phosphate-buffered saline
- HBSS
- Hanks’ balanced salt solution
- BSA
- bovine serum albumin
- Received August 15, 1997.
- Accepted March 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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