339 PHARMACOLOGIC MODULATION BY PGE₁ OF O₂ PRODUCTION BY HUMAN NEUTROPHILS

Abstract

Prostaglandin E₁ (PGE₁), one of a series of naturally occurring prostenoic acid derivatives, has been pharmacologically exploited for its potent vasodilatory effects. However, the observation that patients with patient ductus arteriousus infused with PGE₁ may have a higher incidence of wound infection, has led to the speculation that PGE₁ might be used to modulate PMN activity to avoid neutrophil mediated host autoinjury such as occurs in adult respiratory distress syndrome and septic shock capillary leak. Suppression of human PMN NADPH oxidoreductase by PGE₁ was assessed utilizing a continuous, initial-velocity enzyme assay to quantitate lag time, linearity, rate and extent of superoxide anion production. Assays containing ≤10⁻⁹MPGE₁ generated O₂ 15.8±0.8 nmoles/min/10⁶ PMNs, after a lag time of 13.0±0.8 sec. Catalysis was linear for 26.7±2.4 sec after which a gradual decline in activity ensued. Progressive inhibition of O₂ generation was noted at higher PGE₁ concentrations (10⁻⁹M=0%, 10⁻⁸M=16.4%, 10⁻⁷M=34.8%, 10⁻⁶M=58.2%, 10⁻⁵M=100%). No changes in reaction lag time or linearity were noted over these PGE₁ concentrations, however, extent of reaction was severely compromised at PGE₁ ≥ 10⁻⁷M where catalysis was concluded in <1min. Calculation of plateau concentrations of continuously infused PGE₁ indicate that in vivo modulation of PMN activity is realistic. Present findings indicate the potential feasibility for pharmacologic titration of PMN activity by PGE₁ to limit or avoid inflammatory amplification host autoinjury while simultaneously avoiding nosocomial infection.

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