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To review the platelet-activating factor (PAF) signaling system, its regulation, and its dysregulation in acute inflammation and thrombosis and in syndromes that involve these cascades, including sepsis.A summary of published literature from MEDLINE search files and published reviews.PAF, a phospholipid signaling molecule, transmits outside-in signals to intracellular transduction systems and effector mechanisms in a variety of cell types, including key cells of the innate immune and hemostatic systems: neutrophils, monocytes, and platelets. Thus, the PAF signaling system is a point of convergence at which injurious stimuli can trigger and amplify both acute inflammatory and thrombotic cascades. The biological activities of PAF are regulated by several precise mechanisms that, together, constrain and control its action in physiologic inflammation. Unregulated synthesis of PAF or defects in the mechanisms that limit its biological activities have the potential to cause pathologic inflammation and thrombosis. In addition, nonenzymatic generation of oxidized phospholipids that are recognized by the PAF receptor can trigger inflammatory and thrombotic events. There is evidence that the PAF signaling system is dysregulated in sepsis, shock, and traumatic injury and that interruption or termination of its effector responses leads to beneficial outcomes. Plasma PAF acetylhydrolase, an enzyme that hydrolyzes PAF and structurally related oxidized phospholipids, yielding products that are no longer recognized by the PAF receptor, may be a particularly important signal terminator.The PAF signaling system can trigger inflammatory and thrombotic cascades, amplify these cascades when acting with other mediators, and mediate molecular and cellular interactions (cross talk) between inflammation and thrombosis. Evidence from in vitro experiments, studies of experimental animals, and clinical observations in humans indicates that the PAF signaling system is important in sepsis and other syndromes of inflammatory injury and that therapeutic strategies to interrupt or terminate signaling via the PAF signaling system may be useful in these conditions.