NEW MECHANISMS BY WHICH SECRETORY PHOSPHOLIPASE A(2) STIMULATES NEUTROPHILS TO PROVOKE THE RELEASE OF CYTOTOXIC AGENTS

Background: Secretory phospholipase A(2) (sPLA(2)) is a potent proinfl ammatory enzyme that stimulates inflammation through the production of reactive lipids. However, enzymatic inhibitors have been disappointin g in their effectiveness in halting hyperinflammation. Objective: To d etermine whether sPLA(2) acts directly on neutrophil plasma membrane l ipids or via a nonenzymatic mechanism. Design: Isolated neutrophils (P MNs)were incubated with 3 types of sPLA(2), and elastase and superoxid e release from PMNs was measured. Ethyleneglycotetraacetic acid was us ed as a selective enzymatic inhibitor. The PMNs were exposed to sPLA(2 ) in the presence and absence of ethyleneglycotetraacetic acid and the release of elastase was measured. Setting: Urban trauma research labo ratory. Patients: Normal healthy donors of PMNs. Main Outcome Measures : Stimulated release of superoxide and elastase. Results: The sPLA(2) acted directly on plasma membrane lipids to stimulate the PMN to produ ce superoxide and release elastase. This mechanism is blocked with enz ymatic inhibition of sPLA(2). The sPLA(2) also provokes elastase relea se from PMNs independently of its enzymatic function. This mechanism i s not blocked with traditional enzymatic inhibitors. Conclusions: Thes e data indicate that the sPLA(2) can act directly on PMNs to stimulate the release of inflammatory mediators via enzymatic degradation of pl asma membrane lipids. In addition, sPLA(2) can act as a ligand and sti mulate the PMN independently of its enzymatic activity.