Platelet-activating Factor Primes Human Eosinophil Generation of Superoxide

Abstract

Platelet-activating factor (PAF) is a potent inflammatory mediator that can cause airway obstruction and hyperresponsiveness; these processes are also associated with pulmonary eosinophilia, suggesting a link between these two events. Thus, PAF's interaction with eosinophils may provide a mechanism for airway damage. However, direct in vitro activation of eosinophils by PAF requires concentrations that are likely higher than those achieved in vivo. As a result, we investigated whether lower, more physiologic concentrations of PAF could prime eosinophils for subsequent activation to another receptor-stimulated factor, in this case formylmethionylleucylphenylalanine (FMLP). To test this hypothesis, eosinophils were preincubated (1 and 15 min) with low concentrations of PAF (1 x 10(-8) and 1 x 10(-10) M); this exposure to PAF resulted in enhanced generation of superoxide anion to FMLP stimulation. Moreover, similar concentrations of PAF decreased eosinophil density and increased expression of cell surface CR3 receptors. Finally, low, nonactivating concentrations of PAF (1 x 10(-10) to 1 x 10(-8) M) caused transient increases in eosinophil cytosolic free Ca2+ concentrations. Collectively, these responses are consistent with the hypothesis that short-term exposure to low concentrations of PAF primes eosinophils to cause an enhanced inflammatory response upon subsequent activation to another receptor agonist. The consequences of this PAF-associated phenomenon can produce an enhanced inflammatory response and airway injury.

Endothelial cells upregulate eosinophil superoxide generation via VCAM‐1 expression

“…Moreover, local production of PAF appears to be important not only for the chemotaxis of EOS, but also for their in vitro activation and adhesion to endothelial cells [30,[49][50][51]. PAF is also an EOS-specific primer of cell respiratory burst when stimulated with FMLP [31]. Finally, EOS transmigration across IL-1 and IL-4 treated endothelial cell monolayers is dependent on PAF [27], while increasing the avidity of VCAM-1 binding blocks EOS migration [52].…”

“…Moreover, endothelial cell expression of PAF, and PAF activation of CD11/CD18, is required for optimal neutrophil adhesion [28]. To determine whether PAF was involved in the development of enhanced O 2 generation by EOS adherent to IL-4 þ TNFa-stimulated HUVEC, 20 mM WEB 2086 [29,30], a PAF antagonist which was confirmed to block PAF-induced EOS O 2 generation [30,31], or buffer was added to the EOS/ HUVEC incubation. EOS adhesion to cytokine-treated HUVEC and subsequent O 2 generation to FMLP þ CB were then determined.…”

Pharmacological comparison of LTB4‐induced NADPH oxidase activation in adherent and non‐adherent guinea‐pig eosinophils

“…Furthermore, pre-incubation with subthreshold concentrations of PAF has been demonstrated to prime the subsequent NADPH oxidase response to opsonized particles (Tool et al, 1992) and fMLP (Zoratti et al, 1992). More recent studies have demonstrated NADPH oxidase activation following human eosinophils adhesion to tissue culture plates coated with a range of extracellular matrix proteins (e.g.…”

Differential effects of the PAF receptor antagonist UK‐74,505 on neutrophil and eosinophil accumulation in guinea‐pig skin

“…By acting on specific cell surface receptors (Hanahan, 1986;Kroegel et al, 1989b), PAF can stimulate neutrophils and eosinophils in vitro inducing chemotaxis, adhesion and degranulation (Hanahan, 1986;Wardlaw et al, 1986;Kimani et al, 1988;Czarnetzki & Csato, 1989;Kroegel et al, 1989a). In addition to activating cells directly, PAF can act as a priming agent for eosinophils (Blom et al, 1992;Zoratti et al, 1992). In vivo, intradermal administration of PAF causes neutrophil and eosinophil accumulation and oedema formation in a number of species including guineapigs (Faccioli et al, 1991), horses (Foster et al, 1992a,b), and rabbits (Wedmore & Williams, 1981b;Humphrey et al, 1982;Colditz & Movat, 1984a).…”