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

Abstract

SUMMARYPlatelet-activating factor (PAF) is a proinflammatory agent in infectious and inflammatory diseases, partly due to the activation of infiltrating phagocytes. PAF exerts its actions after binding to a monospecific PAF receptor (PAFR). The potent bioactivity is reflected by its ability to activate neutrophils at picomolar concentrations, as defined by changes in levels of intracellular Ca 21 ([Ca 21 ] i ), and induction of chemotaxis and actin polymerization 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 various neutrophil functions were compared with the effect of recombinant human plasma-derived PAF-acetylhydrolase (rPAF-AH), as an important enzyme for PAF degradation in blood and extracellular fluids. We found that endogenously produced PAF (±like) substances were involved in the spontaneous apoptosis of neutrophils. At concentrations of 8 mg/ml or higher than normal plasma 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 mg/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 of rPAF-AH toward neutrophils was substantiated by its inhibition of PAF-induced chemotaxis and changes in [Ca 21 ] 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.

Dimethyl fumarate modulates neutrophil extracellular trap formation in a glutathione‐ and superoxide‐dependent manner

“…Indeed, in line with our results, DMF was previously suggested to inhibit NET formation in murine autoimmune blistering disease . Notably, we demonstrate that this modulation is stimulus specific: while PMA‐induced, Nox‐dependent NET formation was inhibited, PAF‐ and ionomycin‐induced, probably Nox‐independent NET formation was not inhibited.…”

“…S1c; see Supporting Information). Notably, DMF also did not affect NET formation induced by PAF, which was shown to be incapable of activating Nox without cofactors (see Fig. e).…”

Dissociation of the PAF‐receptor from NADPH oxidase and adenylate cyclase in human neutrophils results in accelerated influx and delayed clearance of cytosolic calcium

“…A possible relationship between PAF‐mediated mobilization of Ca 2+ and ‘priming’ of neutrophils for activation with a second stimulus is supported by the observations that dibutyryl cyclic AMP, CGS 21680 and rolipram all attenuated the sensitizing effects of PAF on FMLP/CB‐activated release of elastase by the cells. These findings also suggest that cyclic AMP‐elevating agents, presumably by enhancement of clearance of Ca 2+ from the cytosol of activated neutrophils, may represent a possible therapeutic alternative to PAF‐receptor antagonists and ‐hydrolyzing enzymes (Kuijpers et al ., 2001).…”

The emerging roles of PAF acetylhydrolase

“…Moreover, over-expression of either the plasma (43)(44)(45) or liver type II (14,46) PAF-AH blocks apoptosis in response to diverse physiologic and pharmacologic agents. The clear implication of these data is that the short-chain phospholipid substrates of these enzymes are distinctly proapoptotic and that these lipids play a large part in regulated cell death.…”