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INTRODUCTION

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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

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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

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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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Figure 37–1

Metabolism of AA. Cyclic endoperoxides (PGG2 and PGH2) arise from the sequential COX and hydroperoxidase actions of COX-1 or COX-2 on AA released from membrane phospholipids. Subsequent products are generated by tissue-specific synthases and transduce their effects via membrane-bound receptors (blue boxes). EETs and isoprostanes are generated via CYP activity and nonenzymatic free radical attack, respectively. Aspirin and nonselective NSAIDs are nonselective inhibitors of COX-1 and COX-2 but do not affect LOX activity. See the text and the Abbreviations list for further definitions.

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