Membrane lipids supply the substrate for the synthesis of eicosanoids and platelet-activating factor (PAF). Arachidonic acid (AA) metabolites, including PGs (prostaglandins), PGI2 (prostacyclin), TxA2 (thromboxane A2), LTs (leukotrienes), and epoxygenase products of cytochromes P450 (CYP)s, 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 for further metabolism. 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, gastrointestinal (GI) mucosal integrity, and stem cell function. They are also important mediators of innate immunity and inflammation. Several classes of drugs, most notably NSAIDs (nonsteroidal anti-inflammatory drugs) (see Chapter 42), including aspirin, owe their principal therapeutic effects—relief of inflammatory pain and antipyresis—to blockade of PG formation.
Abbreviations
15-PGDH: 15-hydroxyprostaglandin dehydrogenase
AA: arachidonic acid
ACTH: corticotropin (formerly adrenocorticotrophic hormone)
AERD: aspirin-exacerbated respiratory disease
AGEPC: acetyl glyceryl ether phosphorylcholine
APRL: antihypertensive polar renal lipid
BLT: leukotriene B4 receptor
COX: cyclooxygenase
CYP: cytochrome P450
CysLT: cysteinyl leukotriene
CysLTr: cysteinyl leukotriene receptor
DPr: prostaglandin D2 receptor
EDHF: endothelium-derived hyperpolarizing factor
EET: epoxyeicosatrienoic acid
EPA: 5,8,11,14,17-eicosapentaenoic acid
EPr: prostaglandin E2 receptor
FLAP: 5-lipoxygenase-activating protein
fMLP: formyl-methionyl-leucyl-phenylalanine
FPr: prostaglandin F2α receptor
GI: gastrointestinal
GPCR: G protein-coupled receptor
HETE: hydroxyeicosatetraenoic acid
H-PGDS: hematopoietic prostaglandin D synthase
HPETE: hydroperoxyeicosatetraenoic acid
IL: interleukin
IPr: prostacyclin receptor
LOX: lipoxygenase
LT: leukotriene
LX_: lipoxin, e.g., LXA, LXB
mPGES-1: microsomal prostaglandin E synthase-1
NO: nitric oxide
NSAID: nonsteroidal anti-inflammatory drug
PAF: platelet-activating factor
PAF-AH: platelet-activating factor acetylhydrolase
PAH: pulmonary arterial hypertension
PD-1: programmed cell death 1
PD-L1: programmed cell death 1 ligand
PG: prostaglandin
PGI2: prostaglandin I2 (prostacyclin)
PGT: prostaglandin transporter
PL: phospholipase, e.g., PLA, PLC
PMN: polymorphonuclear leukocyte
POX: peroxidase
oxPL: oxidized phospholipid
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2
TNF: tumor necrosis factor
TPr: thromboxane A2 receptor
TxA2: thromboxane A2
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 41–1), and 5,8,11,14,17-eicosapentaenoic acid (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.