The impact of platelet-activating factor (PAF)-like mediators on the functional activity of neutrophils: anti-inflammatory effects of human PAF-acetylhydrolase

Platelet-activating factor (PAF) is a proinflammatory agent in infectious a nd inflammatory diseases, partly due to the activation of infiltrating phag ocytes. PAF exerts its actions after binding to a monospecific PAF receptor (PAFR). The potent bioactivity is reflected by its ability to activate neu trophils at picomolar concentrations, as defined by changes in levels of in tracellular Ca2+ ([Ca2+](i)), and induction of chemotaxis and actin polymer ization at nanomolar concentration. The role of PAF in neutrophil survival is, however, less well appreciated. In this study, the inhibitory effects of synthetic PAFR-antagonists on vari ous neutrophil functions were compared with the effect of recombinant human plasma-derived PAF-acetylhydrolase (rPAF-AH), as an important enzyme for P AF degradation in blood and extracellular fluids. We found that endogenousl y produced PAF (-like) substances were involved in the spontaneous apoptosi s of neutrophils. At concentrations of 8 mug/ml or higher than normal plasm a levels, rPAF-AH prevented spontaneous neutrophil apoptosis (21 +/- 4% of surviving cells (mean +/- SD; control) versus 62 +/- 12% of surviving cells (mean +/- SD; rPAF-AH 20 mug/ml); P < 0.01), during overnight cultures of 15 h. This effect depended on intact enzymatic activity of rPAF-AH and was not due to the resulting product lyso-PAF. The anti-inflammatory activity o f rPAF-AH toward neutrophils was substantiated by its inhibition of PAF-ind uced chemotaxis and changes in [Ca2+](i). In conclusion, the efficient and stable enzymatic activity of rPAF-AH over so many hours of coculture with neutrophils demonstrates the potential for its use in the many inflammatory processes in which PAF (-like) substances are believed to be involved.