Platelet-activating factor (PAF) is an important, perhaps pivotal, autacoid with a myriad of phlogistic actions which implicates this mediator in playing an important role in modulating many aspects of normal as well as abnormal (patho)physiological and inflammatory processes. Most all of our current understanding of the mechanisms underlying the (patho)biological actions of PAF has been derived from studies that employed only the hexadecyl-(C16:0) or octadecyl-(C18:0) alkyl chain PAF homologs. However, it is now well-documented that the PAF synthesized by stimulated neutrophils (PMN), as well as by other cells and tissues, is comprised of a heterogeneous family of sn-2 acetylated phospholipids. Moreover, there is now compelling evidence that various PAF homologs and analogs differ significantly from one another in their instrinsic in vitro and in vivo biological activities and potencies (e.g., platelet and PMN stimulation and cardiovascular and pulmonary alterations), possibly by interacting with different PAF receptor subtypes. Therefore, new research initiatives are required to rigorously elucidate the extent of PAF molecular heterogeneity and to characterize the (patho)physiological properties and mechanisms of action of the various PAF molecules. In this regard, the overall objective of the present study will be to address the following hypothesis: Modulation of the types and amounts of the various molecular species of PAF that are synthesized and released by the human PMN will significantly influence the extent and character of PAF-mediated tissue injury and dysfunction. Our investigations will focus on three Specific Aims: 1) Characterization of the molecular composition of the PAF that is synthesized and then either retained or released by human PMN after stimulation by different stimuli; 2) Elucidation of the influence of the intracellular and extracellular microenvironments on the molecular composition of the PAF that is synthesized and then either retained or released by stimulated human PMN; and 3) Characterization of the mechanistic basis for the autocrine actions (agonistic, synergistic, and/or antagonistic) of the PAF homologs and analogs that are synthesized by the human PMN. The results of these studies will provide new information which will be essential in our long-term efforts toward understanding the role of PAF in the modulation of acute inflammatory and allergic tissue injury and dysfunction.
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