New mechanisms by which secretory phospholipase A2 stimulates neutrophils to provoke the release of cytotoxic agents.
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.


METHODS
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.


METHODS
Urban trauma research laboratory.


METHODS
Normal healthy donors of PMNs.


METHODS
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.
Zallen
G
G
Department of Surgery, Denver Health Medical Center, Colo 80204, USA.
Moore
E E
EE
Johnson
J L
JL
Tamura
D Y
DY
Barkin
M
M
Stockinger
H
H
Silliman
C C
CC
D000818:Animals; D004533:Egtazic Acid / Q000494:pharmacology; D017815:Elapidae / Q000276:immunology; D054501:Group II Phospholipases A2; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D009102:Multiple Organ Failure / Q000276:immunology; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000276:immunology*; D010741:Phospholipases A / Q000502:physiology*; D054467:Phospholipases A2; D017382:Reactive Oxygen Species / Q000276:immunology*; D016897:Respiratory Burst / Q000276:immunology; D013481:Superoxides / Q000276:immunology*
D017382:Reactive Oxygen Species; D013481:Superoxides; D004533:Egtazic Acid; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D010196:Pancreatic Elastase