Since its discovery over 20 years ago, platelet- activating factor (PAF) has been the subject of intensive research. In particular, its role in pathophysiology has provoked as much controversy as research interest. The pharmacological profile and ubiquity of PAF have made it a candidate for involvement in a number of inflammatory processes. No clear evidence has been demonstrated however to establish a role in disease in man, although clinical caution about its potential toxic effects has limited the number of available experimental human models. One particular tissue which lends itself to examination of the effects of PAF is the skin. A series of studies has been undertaken to define accurately the characteristics of the acute responses to PAF in human skin and to study the role of histamine in these responses. By way of comparison, the acute responses to other inflammatory mediators (PGE2, substance P, and CGRP) has also been investigated. The effects of histamine antagonism, and depletion on the PAF responses have been examined together with evaluation of local histamine release from the skin after PAF treatment. Additionally, a comparison of the PAF-induced responses in atopic and non-atopic subjects has been undertaken. As a consequence of these studies, quantitative methods have been validated as sensitive and reproducible techniques for evaluating hyperalgesia and histamine-type flare and weal responses in the skin. Using the hyperalgesia model, intradermally injected PAF failed to cause hyperalgesia in the skin. Conversely intradermal PGE2 was shown to provoke dose- related hyperalgesia, which was associated with spreading erythema, lasting for 2-3 hours. Apart from at high doses where the effect was marginal when compared with PGE2, the neuropeptides substance P and CGRP also failed to produce hyperalgesia in the skin. Using the flare and weal model, PAF, substance P and PGE2 were associated with dose-related histamine-like weal and flare responses, although the PGE2 responses were considerably weaker. CGRP did not produce these responses and instead caused a local intense erythema, similar to the later effect of PGE2. Evaluation of the effects of H1-antagonism and histamine depletion, and the quantification of local histamine release have demonstrated that the PAF responses in the skin are largely mediated by histamine. Indomethacin was also found to have a small inhibitory effect on the PAF responses implicating secondary prostaglandin release. The acute inflammatory responses to intradermal PAF have been shown to be similar in atopic subjects compared with non-atopics using the techniques described above. Baseline plasma histamine, however, was found to be higher in atopic subjects
