PAF was first introduced into the literature in 1966 when Barbaro and Zvaifler described a substance that caused antigen induced histamine release from rabbit platelets producing antibodies in passive cutaneous anaphylaxis [16]. Almost four years later, Henson described a ‘soluble factor’ released from leukocytes that induced vasoactive amine release in platelets. Further observations by Siraganuan and Osler [17] described the existence of a diluted substance that had the capacity to cause platelet activation. A year later Jacques Benveniste and colleagues elaborated on the findings of the previous two studies and described a novel factor that induced aggregation and secretion of platelets, which participated in a leukocyte-dependent histamine release from rabbit platelets [18]. Hence, the term platelet-activating factor (PAF) was coined because of the initial observations of its effects on platelets [18]. It was later discerned that PAF was a lipid-like molecule [19]. It is recalled that to study PAF Benveniste prepared a measure of PAF from 100 L of hog blood, which resulted in a 100 L solution from which 1 µL was sufficient to induce platelet aggregation, indicating its high level of potency [20]. However, this amount of PAF was too low to use techniques at the time such as mass spectrometry or magnetic resonance that might determine the structure of the bioactive compound [20]. Despite the lack of structural data, Benveniste and others had determined several of the physical characteristics of PAF. They determined that it was a lipid compound, it could bind to albumin, and it migrated between lysolecithin and sphingomyelin in thin-layer chromatography separation, all properties of which were similar to that of lysophosphatidylcholine. The compound was also affected by several phospholipases (PLA₂, PLC, and PLD) but resistant to others (sphingomyelinase C and PLA₁), indicating that indeed it had a phospholipid type structure [20,21]. Studies began to discern that PAF was implicated in IgE anaphylaxis [22] and many of the properties of PAF released during IgE anaphylaxis began to be elucidated [23]. Furthermore, the role of PAF in platelet aggregation was beginning to be further understood by June 1979 [24].

Following several experiments with phospholipases, etc. the structure of PAF was thought to be 2-acyl-sn-glycero-3-phosphocholine (1-lysophosphatidylcholine) [25], but owing to acyl chain migration this molecule was known for its instability and did not demonstrate the biological properties corresponding to PAF [20,26]. Around that time, several other structures were interrogated, and many researchers were involved in discussions as reviewed by Chap [20]. However, on the 10th of October 1979, Constantinos Demopoulos, Neal Pinckard, and Donald Hanahan, from San Antonio Texas published the structure of PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) under the name AcGEPC (Acetyl-glyceryl-ether-phosphocholine), which was shown to have biological activities indistinguishable from that of naturally generated rabbit PAF (Figure 1) [27]. The researchers realised that the AcGEPC they synthesised was indeed the same structure as naturally occurring PAF. Interestingly, nineteen days after the Demopoulos, Pinckard, and Hanahan [27] publication, the same structure was reported by a group led by Fred Snyder who were assessing the properties of an isolated compound in the kidney that was responsible for peculiar biological activity, which was known by them as the antihypertensive polar renomedullary lipid (APRL) [28]. These studies were followed by an article by Benveniste who subsequently proposed the name PAF-acether [29]. Later articles confirmed that synthetically produced PAF initiated identical biological effects to the PAF molecules responsible for IgE-induced systemic anaphylaxis [30], which also caused similar vascular, cardiovascular, and respiratory problems associated with anaphylaxis in rabbits [31] and baboons [32]. In addition, platelets were not required to induce anaphylactic shock in rabbits when injected with synthetic PAF, indicating for the first time that PAF acts via a receptor [33].

Hanahan and colleagues formally confirmed the structure of PAF in 1980 using mass spectrometry and simplified their abbreviation of the molecules name to AGEPC [34]. Likewise, Benveniste and colleagues simplified the name of the PAF precursor to lyso-PAF [35]. As many researchers were working with PAF at the same time, it is reported that there were conflicting attitudes between the groups with reference to what the name of the molecule should be. Furthermore, Chap described the difficulty encountered by Benveniste who was unfortunate not to have elucidated the structure of PAF previous to the other groups [20]. Considering that we now know PAF exhibits a vast diversity of actions and the fact that a myriad of other molecules can activate platelets, it seems ironic that the name PAF is a misnomer [36] that has remained in the literature.

However, that was not the end of Benveniste’s role in determining some of the properties of PAF. Indeed, Benveniste and colleagues provided the first evidence that platelets synthesise PAF [37] and they determined the subcellular localisation of PAF biosynthesis in human neutrophils [38]. However, Benveniste’s important role in the discovery of PAF may be overshadowed by his later controversial research that led to major scientific scandals [20,39,40] that are not the subject of this review. The very first account of the discovery of PAF and its various properties was published in Nature in 1980 by Cusack [41]. The intensive and dedicated research of many scientists involved in the discovery and structural elucidation of PAF in the 70s and 80s set in motion a research field that is ever growing to this day, which has had profound implications to medical research.