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INTRODUCTION

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

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 F 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

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.

Figure 41–1

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 ...

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