CONCENTRATION-DEPENDENT REGULATORY EFFECTS OF PROSTAGLANDIN-E1 ON HUMAN NEUTROPHIL FUNCTION-INVITRO

Prostaglandin E1 (PGE1) has recently been used clinically as a purported modulator of activated neutrophils in certain forms of the adult respiratory distress syndrome (ARDS). We now report that PGE1 does not have a uniform inhibitory effect upon human neutrophil functions in vitro. Cells were first pretreated with PGE1 followed by incubation with either N-formyl-methionyl-leucyl-phenylalanine (FMLP), phorbol myristate acetate (PMA), or C5a. Lysosomal enzyme release (myeloperoxidase, lysozyme), superoxide anion generation, and chemotaxis were then quantitated. PGE, alone lacked any appreciable effect on these neutrophil functions. However, neutrophils pretreated with PGE1 (50 to 100-mu-M) followed by stimulation with FMLP (50 nM) showed as much as 40% inhibition of lysosomal enzyme release compared with control values (p < 0.0005). In contrast, 0.1 nM to 1-mu-M PGE1 enhanced FMLP-stimulated enzyme release as much as 50% above baseline control values (p < 0.05). Preincubation with 0.1 nM PGE, followed by stimulation with variable doses of FMLP also resulted in enhancement of lysosomal enzyme release by as much as 187 +/- 3% of control values. The enhancing but not inhibitory effects of PGE, were reversible with serial washing of the neutrophil preparations. Enhancement of enzyme release was not observed when either PMA or C5a was used as a stimulus after PGE1 pretreatment. However, cells pretreated with PGE1 (50 to 100-mu-M) and subsequently stimulated with C5a showed as much as 40% inhibition of lysosomal enzyme release. Preincubation of neutrophils with PGE1 (1-mu-M) resulted in a slight (15%) enhancement of chemotaxis to FMLP, but it had no significant effect on C5a-induced chemotaxis. In contrast, as much as 75% inhibition of chemotaxis to FMLP was seen at nM concentrations of PGE1 FMLP- and C5a-triggered neutrophil superoxide anion generation was inhibited by PGE1 (0.1 nM to 100-mu-M) by approximately 15 to 65%, whereas only a slight inhibitory effect was seen on PMA-stimulated O2- production at 100-mu-M PGE1. Binding studies with [H-3]FMLP revealed a twofold increase in the number of receptors on neutrophils pretreated with 0.1 nM PGE1, which could account for the FMLP-specific enhancement observed at this dose of PGE1. Our results, particularly with FMLP, indicate that plasma levels attained in patients with ARDS treated with PGE1 may enhance rather than inhibit important proinflammatory activities of neutrophils thought to play a role in the pathogenesis of this syndrome, especially in patients with sepsis-induced ARDS.