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Friday, June 5, 2015

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

Platelet-activating factor (PAF) is a potent phospholipid-derived mediator thought to play a pivotal role in the etiology of numerous immune and inflammatory conditions. Our knowledge of its effects has broadened to include those as a vasodilator and broncho-constrictor, a contributor to host defenses, and a mediatory of the inflammatory response, and PAF has been well-demonstrated in experimental models to function as a central mediator of anaphylaxis. Gill et al review what we know (J Allergy Clin Immunol 2015; 135(6): 1424-32).

PAF is produced and secreted by several types of cells including mast cells, monocytes, tissue macrophages, eosinophils, endothelial cells, neutrophils, and platelets. It is implicated in platelet aggregation and activation through release of vasoactive amines in the inflammatory response, resulting in effects including increased vascular permeability, circulatory collapse, and decreased cardiac output. Studies have shown patients with acute allergic reactions had elevated PAF serum levels, and patients with severe anaphylaxis had higher levels still. The latter group had respiratory or cardiovascular compromise, where both organ systems were targets of PAF bioactivity.

PAF is rapidly hydrolyzed and degraded to an inactive metabolite, lysoPAF, by the enzyme PAF-acetylhydrolase (PAF-AH), whose activity correlates inversely with PAF levels and predisposition to severe anaphylaxis. Several studies have confirmed more rapid rates of inactivation of PAF result in milder allergic manifestations. There is much interest around the development of therapies that selectively block the actions of PAF as both long-term prophylaxis and emergency treatment. In animal models, treatment with platelet-activating factor receptor (PAF-R) antagonists significantly reduced the severity of peanut-induced anaphylaxis and accelerated recovery from anaphylactic reactions. We are, however, still in the early stages of understanding PAF signaling, and further investigation of its role in pathology and therapeutic modulation is anticipated.

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