Platelet activating factor PAF

Platelet activating factor (PAF) is the term used to describe a family of structurally-related lipids that are all acetylated phosphoglycerides (Fig. 

If the R.2 group of the the substrate 1 - O-alkyl-2-acyl-sn-glycero-3-phos -phocholine is arachidonic acid (i.e. if the PAF molecule is l-O-alkyl-2- 

Not all of the newly-synthesised PAF is released by neutrophils it is thought that release of PAF only occurs after a critical intracellular concentration has been reached even then, some PAF remains cell associated and does not act as a true extracellular effector molecule. The cell-associated PAF may thus play a role in cell-cell communication (e.g. neutrophil-neutrophil or neutrophil-endothelium interactions). Intra- and extracellular Ca2+ levels regulate both the biosynthesis and release of PAF. Increases in intracellular Ca2+ may allow PAF synthesis (but not release), whereas extracellular Ca2+ increases both synthesis and release in a dose-dependent manner. 

The levels of PAF synthesis and release are also modulated by levels of extracellular albumin. In the absence of albumin, neutrophils (stimulated with fMet-Leu-Phe) synthesise only low levels of PAF within 1-2 min of stimulation. In the presence of 0.25% albumin, PAF synthesis is increased, and up to half of this may be released with 5% albumin, rates of synthesis and release are increased further and sustained over a 30-min period. Newly-synthesised PAF is reincorporated by neutrophils into membrane lipids and is therefore poorly soluble in aqueous media. Thus, extracellularly added albumin will bind to cell-associated PAF and effectively solubilise it at concentrations below its critical micellar concentration (CMC). This will effectively enhance the PAF release rate, which will decrease the concentration of cell-associated PAF thus, the rate of biosynthesis will be sustained. 

---

The synthetic utihty of the above transformations stems from the fact that many monoesters obtained as a result of hydrolysis may be converted to pharmaceutically important intermediates. For example, the optically active glycerol derivative (27) is a key intermediate in the production of P-blockers. Akyl derivative (25) may be converted into (5)-paraconic acid [4694-66-0] ((5)-5-oxo-3-tetrahydrofurancarboxyhc acid) that is a starting material for the synthesis of (3R)-A-factor. The unsaturated chiral cycHc monoacetate (31) is an optically active synthon for prostaglandins, and the monoester (29) is used for the synthesis of platelet activating factor (PAF) antagonists. 

Platelet activating factor (PAF) was first identified by its ability (at low levels) to cause platelet aggregation and dilation of blood vessels, but it is now known to be a potent mediator in inflammation, allergic responses, and shock. PAF effects are observed at tissue concentrations as low as 10 M. PAF causes a dramatic inflammation of air passages and induces asthma-like symptoms in laboratory animals. Toxic-shock syndrome occurs when fragments of destroyed bacteria act as toxins and induce the synthesis of PAF. This results in a drop in blood pressure and a reduced... 

Vadas P, Gold M, Perelman B, Liss GM, Lack G, Blyth T Simons FE, Simons JK, Cass D, Yeung J Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. N Engl J Med 2008 358 28-35. 

Figure 24-4. Biosynthesis of ether lipids, including plasmalogens, and platelet-activating factor (PAF). In the de novo pathway for PAF synthesis, acetyl-CoA is incorporated at stage, avoiding the last two steps in the pathway shown here.

Plasmalogens and platelet-activating factor (PAF) are ether phospholipids formed from dihydroxyacetone phosphate. 

Histamine Serotonin Platelet-activating factor (PAF) Eicosanoids (various prostaglandins and leukotrienes) C3a, C4a, and C5a from the complement system Bradykinin and fibrin split products from the coagulation system... 

K5. Kawamura, M Terashita, Z Imura, Y., Shino, A., and Nishikawa, K Inhibitory effect of TCV-309, a novel platelet activating factor (PAF) antagonist, on endotoxin-induced disseminated intravascular coagulation in rats Possible role of PAF in tissue factor generation. Thromb. Res. 70,281-293(1993). 

It is possible that nematode-secreted AChEs act on alternative substrates to ACh. We had previously suggested, on the basis of structural similarity, that platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, might represent such an alternative substrate (Blackburn and Selkirk, 1992b) but subsequent studies demonstrated that purified AChEs did not cleave PAF, and the enzyme responsible for this activity in secreted products of N. brasiliensis, PAF acetylhydrolase, was purified and defined as a distinct heterodimeric protein (Grigg et al., 1996). Although an open mind on the subject sould be kept, the strict substrate specificity of the nematode-secreted AChEs suggests that they most likely act on ACh alone. 

Bito, H., Nakamura, M., Honda, Z. etal. Platelet-activating factor (PAF) receptor in rat brain PAF mobilizes intracellular Ca2+ in hippocampal neurons. Neuron 9 285-294, 1992. 

Mast cell degranulation in response to allergens results in release of mediators such as histamine eosinophil, and neutrophil chemotactic factors leukotrienes C4, D4, and E4 prostaglandins and platelet-activating factor (PAF). Histamine is capable of inducing smooth muscle constriction and bronchospasm and may play a role in mucosal edema and mucus secretion. 

Ishii, S. and Shimizu, T., Platelet-activating factor (PAF) receptor and genetically engineered PAF receptor mutant mice, Prog. Lipid Res. 39, 41-82, 2000. 

Chapter 7 outlines the basic mechanism and treatment of emesis, and in particular, that induced by chemotherapy of cancer. Finally, the chemistry, pharmacology and clinical applications of antagonists of the platelet-activating factor (PAF), an important mediator of many physiological and pathological conditions, are reviewed in Chapter 8. 

---