Platelet-activating factor.

Abstract

Platelet-activating factor is a phospholipid with diverse potent physiological effects. Its actions are achieved at concentrations as low as IO-‘” M in some systems and almost always by lo-’ M as an intercellular messenger. The molecular structure of PAF was discovered through parallel investigations of two different biological activities: a factor in the blood of rabbits undergoing anaphylaxis that activated platelets and a polar lipid from kidneys that lowered blood pressure. The fields merged when the structure of the compound responsible for both responses was shown to be 1-O-alkyl-2-acetyl-snglycero-3-phosphocholine (Fig. 1; reviewed in Refs. 1 and 2). This compound has many actions in addition to activation of platelets: activation of polymorphonuclear leukocytes, monocytes, and macrophages, increased vascular permeability, hypotension, decreased cardiac output, stimulation of glycogenolysis in perfused liver, stimulation of uterine contraction, and others. It appears to function both in normal physiological events and to mediate pathological responses, particularly inflammation and allergy (chapter 10 in Ref. 2). Each feature of the structure of PAF is important for optimal biological activity, and the responses are stereospecific. The ether linkage at the sn-1 position of the glycerol backbone has a marked influence; compounds that are identical except for a fatty acid at sn-1, which are produced by a variety of cells, have less than 1% of the potency of PAF. The fatty alcohol at the sn-1 position usually is hexadecanol, although species with different lengths of the alkyl chain and with double bonds have been identified, and these differences have a modest (severalfold) effect on potency. The acetate residue at the sn-2 position also is important for activity since increasing the chain length beyond 3 carbons diminishes the potency. Synthetic compounds in which the polar head group at the sn-3 position is altered have decreased potency (see chapters 7 and 8 in Ref. 2). Tessner and Wykle (3) showed that stimulated human neutrophils produced compounds with an ethanolamine head group. The majority (80%) of these molecules also had an cu-fl unsaturation in the alkyl chain (lO-alk-l’-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine) and were derived from ethanolamine plasmalogens. Nakayama et al. (4) found the analogous choline phosphoglyceride, l-O-hexadec-l’-enyl-2-acetyl-sn-glycero-3-phosphocholine, in heart muscle. These results have led to disagreement over the suitability of the trivial name, PAF, since it describes only