Platelet-activating factor antagonists - Current status in asthma

Platelet-activating factor (PAF) is a potent lipid-derived mediator of infl ammation that is considered to have a potential role in the pathogenesis of asthma. PAF is produced by many cells associated with asthmatic inflammati on and has the ability to evoke some of the clinical hallmarks of asthma, s uch as bronchoconstriction, mucus production and airway hyperresponsiveness (AHR). In addition, PAF has profound chemoattractant properties for eosino phils and neutrophils and it promotes an increase in microvascular permeabi lity and oedema formation within the airways. Nevertheless, the definitive role of PAF in asthma remains elusive. PAF is formed as a result of the act ion of phospholipase AZ and acetyltransferase on membrane phospholipids and it is degraded by a PAF-specific acetylhydrolase. The biological effects o f PAF are mediated by the activation of specific receptors expressed on eff ector cell surfaces, although intracellular signalling and paracrine action s have been described. Tn addition, at least part of the pulmonary effects of PAF could be related to the secondary release of leukotrienes. In the cl inical setting, different ways of modifying the activity of PAF have been e xplored, in particular the inhibitory actions of PAF receptor antagonists. Both natural and synthetic PAF receptor antagonists have shown conflicting results. Although second generation PAF antagonists (apafant, UK-74505, SR- 27417A) appear to have a good protective effect against the systemic and pu lmonary actions of inhaled PAF, the protective effects of these compounds o n allergen-induced responses and AHR are more modest. In the treatment of a sthma, PAF receptor antagonists have failed to produce a significant impact in either acute asthma attacks or the maintenance therapy of chronic forms . Other pharmacological interventions of proven efficacy in asthma, such as salbutamol or 5-lipoxygenase antagonists, have shown some anti-PAF effects . Whether the overall negative results with PAF receptor antagonists indica te that extracellular PAF is not a relevant mediator of airway inflammation or that the compounds explored are not capable of blocking the paracrine a ctions of PAF remains speculative. A PAF synthase inhibitor could be valuab le in the elucidation of the role of PAF and it might be a promising and us eful complementary therapeutic tool in the future.