PAF (platelet-activating factor) is a family of structurally-related acetylated phospholipids with differing biological potencies; the most active PAF relative to platelet stimulation, is 1-O-hexadecyl-2-acetyl- sn-glycero-3-phosphocholine (C16:0-AGEPC or C16:0- acetyl glyceryl ether phosphocholine). Since the majority of studies to characterize the non- platelet, biological activities of PAF have utilized either C16:0-AGEPC or the 18 carbon homolog, C18:0-AGEPC, little information is available regarding the comparative biological activities of other membranes of the PAF family. Thus, the purpose of the proposed studies is to rigorously define the extent and patterns of concomitant cardiovascular and pulmonary responses following the intravenous bolus administration of various PAF homologs and analogs in the anesthetized, fully- instrumented rabbit. Multiple cardiopulmonary parameters will be continuously estimated including left and right ventricular pressures, mean arterial pressure, and cardiac output as well as lung mechanical and ventilatory events; sequential blood samples will be obtained to evaluate alterations in circulating platelets and white blood cells and to deprive plasma for the detection of platelet factor 4 and selected arachidonic acid metabolites. Second, the contribution of circulating platelets and neutrophils and secondary mediators, e.g., histamine, thromboxane, or leukotrienes, in modulating the cardiopulmonary alterations induced by PAF homologs and analogs will be estimated. Third, the relative efficacy of selected PAF antagonists (which have been developed against either C16:0- or C18:0-AGEPC in platelet bioassay) against PAF homologs and analogs will be examined. Finally, the comparative pathophysiological effects of a sustained infusion of PAF homologs and analogs will be obtained in this same animal model. The results of these studies will provide new and important information regarding the comparative biological activities of PAF homologs and analogs. These results will provide a critically needed foundation to determine the possible role of individual PAF molecules in modulating abnormal cardiopulmonary pathophysiological responses as may occur in allergic or inflammatory disease in man.
| Pinckard, R N; Woodard, D S; Showell, H J et al. (1994) Structural and (patho)physiological diversity of PAF. Clin Rev Allergy 12:329-59 |
| McManus, L M; Woodard, D S; Deavers, S I et al. (1993) PAF molecular heterogeneity: pathobiological implications. Lab Invest 69:639-50 |
