Inhibition of neutrophil activation by p‐bromophenacyl bromide and its effects on phospholipase A2

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Abstract
1 In an effort to elucidate the nature of the inhibitory effects of p-bromophenacyl bromide (pBPB) on neutrophil stimulation, we have examined its effects on several stages of stimulus-response coupling. 2 Pretreatment of rat neutrophils with pBPB resulted in a dose- and time-dependent irreversible inhibition of both N-formylmethionyl-leucylphenylalanine (fMet-Leu-Phe)-induced lysosomal enzyme release and change in transmembrane potential. 3 Inhibition of the biological responses to the chemotactic peptide f Met-Leu-Phe was not due to receptor inactivation since f Met-Leu-[3H]-Phe binding to the formyl peptide receptor was not significantly altered by pBPB pretreatment. 4 Inhibition by pBPB of phorbol myristate acetate (PMA)-induced changes in transmembrane potential and the generation of superoxide (0–2) was also observed. 5 pBPB treatment appeared to inhibit activation of the NADPH oxidase without a direct effect on the oxidase itself. 6 This inhibitory effect was not accompanied by cell death or decrease in cellular titratable sulphydryl groups (at least at doses < 20 μM). 7 There was, however, significant inhibition of a membranous fraction of f Met-Leu-Phe-induced phospholipase A2 activity by pretreatment with 10 μM pBPB, although total cellular phospholipase A2 was only minimally (< 20% inhibition) affected. 8 These data would indicate that pBPB inhibits an early event associated with stimulus-response coupling in rat polymorphonuclear leukocytes (i.e. change in transmembrane potential). The inhibitory effects of pBPB may be secondary to the inhibition of a critical membranous fraction of cell bound phospholipase A2 activity or its activation, necessary for the initiation of cell activation.