PAF is a
phospholipid formed from the action of
phospholipase A2 upon cellular membranes in response to immunologic or hypoxic stimuli. PAF does not exist in its active form as a storage product within cells, but is synthesized rapidly after
phospholipase A2 activation. A potent
lipid released by multiple cell types in mammalian systems, the emerging perspective is that PAF is a major endogenous mediator influencing the pathogenesis and outcome of
ischemia and conditions of circulatory
shock. These effects appear to be especially relevant to the syndrome of MSOF during
critical illness. All of the major criteria for validation of a
shock factor have been fulfilled for PAF. First, PAF has been measured in
biological fluid of animals during
shock states, although this is not an easy task since PAF is formed in minute amounts and is rapidly metabolized. Nevertheless, combinations of high pressure liquid chromatography (HPLC) and bioassay methods employing washed rabbit platelets have been successfully utilized in this regard. Second, synthetic PAF has been injected into cell
suspensions, isolated tissues, and live animals, where it produces most of the effects attributed to endogenous PAF released by immunologic or hypoxic stimuli. These studies have shown that PAF exerts a variety of pathophysiologic actions, including (1) cardiodepression (that is, a negative inotropic effect), (2) reductions in systemic blood pressure, (3) leakage of fluid from the microvasculature, (4) bronchoconstriction, and (5) platelet aggregation. All of these actions of PAF can initiate or exacerbate
shock and ischemic injury in multiple organ systems. Third, specific PAF receptor antagonists have been found to markedly attenuate the severity of endotoxic, anaphylactic, hemorrhagic, and
traumatic shock, as well as acute
myocardial ischemia. In all these conditions, a variety of PAF receptor antagonists (including PAF analogues and structurally dissimilar substances) have improved survival and have retarded pathophysiologic processes believed to be important in causing tissue injury. These processes include lysosomal membrane damage and proteolysis. Moreover PAF receptor antagonists attenuate the release of secondary toxic factors in
shock, such as
myocardial depressant factor. Thus, administration of specific PAF receptor antagonists early in the course of circulatory
shock and organ
ischemia may prove to be useful therapeutic agents in a variety of life-threatening disorders. In addition to having direct actions, PAF appears to function as a pivotal agent in a chain of mediators producing tissue injury. Recent evidence suggests that
tumor necrosis factors (i.e.,
cachectin) stim