Prostaglandin E1 attenuates cytotoxic mechanisms of primed neutrophils.
In a recent clinical trial, liposomal prostaglandin E1 (PGE1) improved oxygenation, increased compliance, and decreased ventilator dependency in patients with adult respiratory distress syndrome (ARDS), thus renewing interest in PGE1 as a potential modulator of inflammation. The neutrophil (PMN) is believed to play a key role in the development of ARDS. Consequently, we investigated the effects of PGE1 on three components of the neutrophil inflammatory response: reactive oxygen species (ROS) generation, protease release, and surface expression of adhesion molecules. Human neutrophils were incubated with PGE1 and then primed with platelet-activating factor (PAF) and activation with N-formyl-methionyl-leucylphenylalanine (fMLP). PGE1 at a dose range of (10[-8] to 10[-5] M) attenuated primed/activated (PAF/fMLP) PMN superoxide anion generation and elastase release. In contrast, PGE1 doses > or =10[-5] M were required to attenuate PAF-stimulated neutrophil upregulation of CD11b/CD18 adhesion molecules. PGE1 also diminished the duration of the PAF-induced cytosolic calcium (Ca2+) flux. Our results suggest that plasma levels of PGE1 attained in patients with ARDS may attenuate ROS and protease neutrophil cytotoxicity but may not effectively block PMN-endothelial cell (EC) adhesion. This attenuation may occur through abrogation of the Ca2+ influx.
Tamura
D Y
DY
Department of Surgery, Denver Health Medical Center, University of Colorado Health Sciences Center, 80204, USA.
Moore
E E
EE
Partrick
D A
DA
Johnson
J L
JL
Offner
P J
PJ
Silliman
C C
CC
D000527:Alprostadil / Q000494:pharmacology*; D018821:CD18 Antigens / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006801:Humans; D016177:Macrophage-1 Antigen / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation
D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D013481:Superoxides; D010196:Pancreatic Elastase; D000527:Alprostadil; D002118:Calcium