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Membrane lipids supply the substrate for the synthesis of eicosanoids and platelet-activating factor (PAF). Arachidonic acid (AA) metabolites, including PGs, PGI2, TxA2, LTs, and epoxygenase products of CYPs, collectively the eicosanoids, are not stored but are produced by most cells when a variety of physical, chemical, and hormonal stimuli activate acyl hydrolases that make arachidonate available. Membrane glycerophosphocholine derivatives can be modified enzymatically to produce PAF. PAF is formed by a smaller number of cell types, principally leukocytes, platelets, and endothelial cells. Eicosanoids and PAF lipids function as signaling molecules in many biological processes, including the regulation of vascular tone, renal function, hemostasis, parturition, GI mucosal integrity, and stem cell function. They are also important mediators of innate immunity and inflammation. Several classes of drugs, most notably NSAIDs (see Chapter 38), including aspirin, owe their principal therapeutic effects—relief of inflammatory pain and antipyresis—to blockade of PG formation.
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Abbreviations
AA: arachidonic acid
ACTH: corticotropin (formerly adrenocorticotrophic hormone)
BLT1/2: LTB4 receptors
cAMP: cyclic adenosine monophosphate
COX: cyclooxygenase
CYP: cytochrome P450
CysLT: cysteinyl leukotriene
CysLT1/2: CysLT receptors
DP2: a member of the fMLP-receptor superfamily, CRTH2
DP: PGD2 receptor
EDHF: endothelium-derived hyperpolarizing factor
EET: epoxyeicosatrienoic acid
EP: PGE2 receptor
EPA: 5,8,11,14,17-eicosapentaenoic acid
FLAP: 5-LOX–activating protein
FP: PGF2α receptor
fMLP: formyl-methionyl-leucyl-phenylalanine
GPCR: G protein–coupled receptor
HETE: hydroxyeicosatetraenoic acid
HPETE: hydroxyperoxyeicosatetraenoic acid
IL: interleukin
IP3: inositol 1,4,5-trisphosphate
IP: PGI2 receptor
iPLA2: independent PLA2
IsoP: isoprostane
LOX: lipoxygenase
LT: leukotriene
LX*: lipoxin*, e.g., LXA, LXB
NSAID: nonsteroidal anti-inflammatory drug
PAF: platelet-activating factor
PAF-AH: PAF acetylhydrolyase
PG: prostaglandin
PGDH: PG 15-OH dehydrogenase
PGI2: prostacyclin
PL*: phospholipase*, e.g., PLA, PLC
PMN: polymorphonuclear leukocyte
POX: peroxidase
TNF: tumor necrosis factor
TP: TxA2 receptor
TxA: thromboxane A
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Eicosanoids, from the Greek eikosi (“twenty”) are formed from precursor essential fatty acids that contain 20 carbons and 3, 4, or 5 double bonds: 8,11,14-eicosatrienoic acid (dihomo-γ-linolenic acid), 5,8,11,14-eicosatetraenoic acid (AA; Figure 37–1), and EPA. AA is the most abundant precursor, derived from the dietary omega-6 fatty acid, linoleic acid (9,12-octadecadienoic acid), or ingested directly as a dietary constituent. EPA is a major constituent of oils from fatty fish such as salmon.
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