Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking

• Published in: The Journal of clinical investigation Vol. 99; no. 10; pp. 2358 - 2364
• Main Authors: Lehr, H A, Weyrich, A S, Saetzler, R K, Jurek, A, Arfors, K E, Zimmerman, G A, Prescott, S M, McIntyre, T M
• Format: Journal Article
• Language: English
• Published: United States 15.05.1997
• Subjects: Animals; Antioxidants - pharmacology; Ascorbic Acid - pharmacology; Azepines - pharmacology; Blood Platelets - drug effects; Blood Platelets - physiology; Cell Adhesion; Cell Aggregation; Chemokine CCL4; Cricetinae; Humans; Interleukin-8 - blood; Macrophage Inflammatory Proteins - blood; Monocytes - drug effects; Monocytes - physiology; Neutrophils - drug effects; Neutrophils - physiology; Platelet Activating Factor - analogs & derivatives; Platelet Activating Factor - antagonists & inhibitors; Platelet Activating Factor - pharmacology; Platelet Activating Factor - physiology; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Membrane Glycoproteins - antagonists & inhibitors; Platelet Membrane Glycoproteins - physiology; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Reference Values; Smoking - blood; Time Factors; Triazoles - pharmacology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci119417

Cigarette smoking within minutes induces leukocyte adhesion to the vascular wall and formation of intravascular leukocyte-platelet aggregates. We find this is inhibited by platelet-activating factor (PAF) receptor antagonists, and correlates with the accumulation of PAF-like mediators in the blood of cigarette smoke-exposed hamsters. These mediators were PAF-like lipids, formed by nonenzymatic oxidative modification of existing phospholipids, that were distinct from biosynthetic PAF. These PAF-like lipids induced isolated human monocytes and platelets to aggregate, which greatly increased their secretion of IL-8 and macrophage inflammatory protein-1alpha. Both events were blocked by a PAF receptor antagonist. Similarly, blocking the PAF receptor in vivo blocked smoke-induced leukocyte aggregation and pavementing along the vascular wall. Dietary supplementation with the antioxidant vitamin C prevented the accumulation of PAF-like lipids, and it prevented cigarette smoke-induced leukocyte adhesion to the vascular wall and formation of leukocyte-platelet aggregates. This is the first in vivo demonstration of inflammatory phospholipid oxidation products and it suggests a molecular mechanism coupling cigarette smoke with rapid inflammatory changes. Inhibition of PAF-like lipid formation and their intravascular sequela by vitamin C suggests a simple dietary means to reduce smoking-related cardiovascular disease.