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New Mechanisms by Which Secretory Phospholipase A2 Stimulates Neutrophils to Provoke the Release of Cytotoxic Agents
Garret Zallen, MD;
Ernest E. Moore, MD;
Jeffrey L. Johnson, MD;
Douglas Y. Tamura, MD;
Michael Barkin;
Hubertus Stockinger, PhD;
Christopher C. Silliman, MD, PhD
Arch Surg. 1998;133:1229-1233.
Background Secretory phospholipase A2 (sPLA2) 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 sPLA2 acts directly on neutrophil plasma membrane lipids or via a nonenzymatic mechanism.
Design Isolated neutrophils (PMNs) were incubated with 3 types of sPLA2, and elastase and superoxide release from PMNs was measured. Ethyleneglycotetraacetic acid was used as a selective enzymatic inhibitor. The PMNs were exposed to sPLA2 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 sPLA2 acted directly on plasma membrane lipids to stimulate the PMN to produce superoxide and release elastase. This mechanism is blocked with enzymatic inhibition of sPLA2. The sPLA2 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 sPLA2 can act directly on PMNs to stimulate the release of inflammatory mediators via enzymatic degradation of plasma membrane lipids. In addition, sPLA2 can act as a ligand and stimulate the PMN independently of its enzymatic activity.
From the Department of Surgery, Denver Health Medical Center, Denver, Colo (Drs Zallen, Moore, Johnson, and Tamura and Mr Barkin); Department of Biochemicals, Boehringer Mannheim GmbH, Penzberg, Germany (Dr Stockinger); and Department of Pediatrics, University of Colorado, Denver (Dr Silliman).
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