title: Platelet-activating factor (PAF) and PAF antagonists in asthma.
abstract: PAF is produced by and activates inflammatory cells, such as monocytes/macrophages, mast cells, platelets, neutrophils, eosinophils and endothelial cells. Its ability to imitate anaphylaxis, inducing for instance bronchoconstriction (BC) in guinea-pigs, and its identification (and/or that of lyso-PAF) in exudates from shocked lungs, led to the hypothesis that PAF is involved in immediate hypersensitivity. Recent results of Bachelet et al. show that PAF reduces the increased cyclic AMP content of guinea-pig alveolar cell population exposed to PGE2, salbutamol or isoprenaline, which agrees with its hypothesized stimulating role in conditions where increased cyclic AMP may reduce mediator release. PAF antagonists are usually selected with in vitro platelet tests and their in vivo activity is characterized in normal animals. Recent data of Pretolani et al. demonstrate nevertheless that the antagonists may lose part of their ability to inhibit PAF itself if tested on lungs from actively sensitized guinea-pigs. These lungs differ from those of passively sensitized or of naive animals in that they become hyper-responsive to mediators (PAF, leukotriene D4 [LTD4], histamine, arachidonate [AA]): BC and formation of thromboxane A2 are enhanced, and histamine is released dose-dependently under conditions where it is absent from perfusates from LTD4, AA or PAF-stimulated naive lungs. Peripheral inflammatory cells (basophils, eosinophils, monocytes) are possibly recruited into the lungs of the actively sensitized animals sometime during the second and/or third week of sensitization, and provide a new target which may account for the enhanced lung responsiveness. Ultra-structural studies of Lellouch-Tubiana et al. (abstract in this meeting) support this concept. Neither the primary target nor the chemotactic substance responsible for the reported modifications are identified, but recent data of Bachelet et al, showing that alveolar populations from actively sensitized guinea-pigs are less responsive to the cyclic AMP stimulating effects of PGE2, salbutamol or isoprenaline suggest the existence of a cell defect which may be important for the triggering of allergen-induced BC and cell recruitment. Our present concept involves a "pre-inflamed" lung in actively sensitized guinea-pigs and in human asthmatics, a stand-by process following sensitization and which is revealed following the activation of a target cell. This may be the alveolar macrophage which releases substances (PAF, TXA2, IL1) likely to start BC and protracted cell recruitment and activation.
authors.affiliation: Institut Henri Beaufour, Le Plessis, France.
authors.forename: D
authors.initials: D
authors.lastname: Hosford
authors.forename: J M
authors.initials: JM
authors.lastname: Mencia-Huerta
authors.forename: P
authors.initials: P
authors.lastname: Braquet
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D006967:Hypersensitivity / Q000503:physiopathology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D010972:Platelet Activating Factor