Platelet-activating factors (PAFs), acetylated phosphoglycerides produced by a variety of inflammatory cells, possess a remarkable spectrum of biological activities associated with cardiopulmonary alternations and acute vascular tissue injury. Recent studies have demonstrated that PAF synthesized and released by stimulated human polymorphonuclear leukocytes (PMN) is comprised of multiple molecular species. These PAFs differ in their relative biological potencies thus, having profound implications regarding the role of these mediators in the pathogenesis of cardiovascular and pulmonary disease processes. In this regard, alternations in the homeostatic mechanisms modulating the synthesis and the release of PAFs may be a key factor involved in the pathological potential of these inflammatory mediators. Indeed, evidence now indicates that the amount and duration of PAF synthesized by stimulated PMN is tightly coupled to the ability of the PMN to release the newly-synthesized PAF. However, the distribution of the molecular species of PAF has not been investigated relative to stimulus-specific PAF synthesis-release coupling in activated PMN. Thus, to be able to more clearly define the regulation of the synthesis and release of PAF as may also occur in inflammatory tissue injury, the following objectives must be accomplished: 1) to determine the distribution of molecular species of PAF synthesized and released from PMN activated with diverse stimuli; 2) to comprehensively characterize PAF phospholipid precursors in PMN; 3) to evaluate the regulatory role of enzymes involved in PAF metabolism in stimulated PMN; and 4) to determine the effects of PAF receptor antagonists and analogs on the synthesis and release of PAF from stimulated PMN. Elucidation of these objectives will provide new and valuable information which may be useful in future studies designed to prevent or treat PAF-mediated inflammatory diseases affecting man.
