PROSTAGLANDIN E-1 ATTENUATES CYTOTOXIC MECHANISMS OF PRIMED NEUTROPHILS

In a recent clinical trial, liposomal prostaglandin E-1 (PGE(1)) impro ved oxygenation, increased compliance, and decreased ventilator depend ency in patients with adult respiratory distress syndrome (ARDS), thus renewing interest in PGE(1) as a potential modulator of inflammation. The neutrophil (PMN) is believed to play a key role in the developmen t of ARDS. Consequently, we investigated the effects of PGE(1) on thre e components of the neutrophil inflammatory response: reactive oxygen species (ROS) generation, protease release, and surface expression of adhesion molecules. Human neutrophils were incubated with PGE(1) and t hen primed with platelet-activating factor (PAF) and activation with N -formyl-methionyl-leucyl-phenylalanine (fMLP). PGE(1) at a dose range of (10(-8) to 10(-5) M) attenuated primed/activated (PAF/fMLP) PMN sup eroxide anion generation and elastase release. In contrast, PGE(1) dos es greater than or equal to 10(-5) M were required to attenuate PAF-st imulated neutrophil upregulation of CD11b/CD18 adhesion molecules. PGE (1) also diminished the duration of the PAF-induced cytosolic calcium (Ca2+) flux. Our results suggest that plasma levels of PGE(1) attained in patients with ARDS may attenuate ROS and protease neutrophil cytot oxicity but may not effectively block PMN-endothelial cell (EC) adhesi on. This attenuation may occur through abrogation of the Ca2+ influx.