New Mechanisms by Which Secretory Phospholipase A2 Stimulates Neutrophils to Provoke the Release of Cytotoxic Agents

Background Secretory phospholipase A 2 (sPLA 2 ) is a potent proinflammatory enzyme that stimulates inflammation through the production of reactive lipids. However, enzymatic inhibitors have been disappointing in their effectiveness in halting hyperinflammation. Objective To determine whether sPLA 2 acts directly on neutrophil plasma membrane lipids or via a nonenzymatic mechanism. Design Isolated neutrophils (PMNs) were incubated with 3 types of sPLA 2 , and elastase and superoxide release from PMNs was measured. Ethyleneglycotetraacetic acid was used 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 laboratory. 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 produce superoxide and release elastase. This mechanism is blocked with enzymatic inhibition of sPLA 2 . The sPLA 2 also provokes elastase release from PMNs independently of its enzymatic function. This mechanism is not blocked with traditional enzymatic inhibitors. Conclusions These data indicate that the sPLA 2 can act directly on PMNs to stimulate the release of inflammatory mediators via enzymatic degradation of plasma membrane lipids. In addition, sPLA 2 can act as a ligand and stimulate the PMN independently of its enzymatic activity.