Evidence that platelet activating factor may mediate some acute inflammatory responses. Studies with the platelet-activating factor antagonist, CV3988.
Platelet activating factor (PAF) has many proinflammatory properties. It is a polymorphonuclear leukocyte chemotactic factor, it aggregates platelets, increases vascular permeability, and is generated by inflammatory cells. To determine the possible in vivo role of PAF in inflammation, we examined the effects of the PAF antagonist and structural analogue, CV3988 on acute inflammatory responses in the skin of rabbits. Initial experiments indicated that CV3988 (10 mg/kg) was a specific inhibitor of PAF responses in vivo since it abolished neutropenia and thrombocytopenia induced by intravenous (iv) PAF infusion without effecting the response to f-met-leu-phe. In dermal inflammation, 125I-albumin, 111In-labeled platelets, 51Cr-labeled leukocytes, and 86RbCl were used to simultaneously quantitate protein exudation, platelet deposition, leukocyte accumulation, and blood flow in the lesions. CV3988 inhibited inflammatory responses to intradermal injection of PAF by 65 to 85% but it did not inhibit thrombin-induced platelet deposition or bradykinin and histamine-induced protein exudation. CV3988 treatment inhibited by 60 to 80% (p less than 0.01) the platelet deposition occurring at the peak of the reaction (1 1/2 hours) induced by the intradermal injection of zymosan, zymosan activated plasma, endotoxin, and the reversed passive Arthus reaction. Protein exudation was inhibited by 67 to 85% (p less than 0.1) and leukocyte accumulation was inhibited by 24 to 35% (p less than 0.05), but only in the zymosan and reversed passive Arthus reactions, respectively. Inflammatory hyperemia (increases blood flow) was not affected by CV3988 treatment. We conclude that in certain inflammatory reactions, PAF may mediate platelet deposition and protein exudation. The marginal effect of CV3988 on leukocyte accumulation suggests that the leukotactic activity of PAF is relatively less important in vivo.
D000208:Acute Disease; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D007249:Inflammation / Q000097:blood / Q000503:physiopathology*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors; D009503:Neutropenia / Q000517:prevention & control; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D012709:Serum Albumin / Q000378:metabolism; D012867:Skin / Q000098:blood supply; D013844:Thiazoles / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000517:prevention & control
D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D012709:Serum Albumin; D013844:Thiazoles; D009240:N-Formylmethionine Leucyl-Phenylalanine; C037913:CV 3988