Prostaglandins, Leukotrienes, and Lipoxins

Prostaglandins are a group of compounds related to the unsaturated fatty acids. They were discovered in the 1930s, when it was found that human semen contained substances that could stimulate smooth muscle tissue, such as uterine muscle, to contract. On the assumption that these substances came from the prostate gland, they were named prostaglandins. We now know that prostaglandins are widely distributed in almost all human tissues, that they are biologically active in minute concentration, and that they have various effects on fat metabolism, heart rate, and blood pressure. 

Prostaglandins have 20 carbon atoms. They are synthesized in the body by oxidation and cyclization of the 20-carbon unsaturated fatty acid arachidonic acid. Carbon-8 through carbon-12 of the chain are looped to form a cyclopentane ring, and an oxygen function (carbonyl or hydroxyl group) is always present at carbon-9. Various numbers of double bonds or hydroxyl groups may also be present elsewhere in the structure. 

Prostaglandins are biosynthesized from the 20-carbon unsaturated fatty acid, arachidonic acid. Leukotrienes and lipoxins 

Prostaglandins have excited much interest in the medical community, where they are used in the treatment of inflammatory diseases, such as asthma and rheumatoid arthritis treatment of peptic ulcers control of hypertension regulation of blood pressure and metabolism and inducing of labor and therapeutic abortions. 

Enzymatic oxidation of arachidonic acid also leads to two important classes of acyclic products, leukotrienes and lipoxins, that arise from oxidation at C-5 and/or C-15. 

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In this review, we first describe the paths and enzymes leading to prostaglandins, leukotrienes, and lipoxins. We then take each of our topics, separately dealing with leukotriene modulators followed by cyclooxygenase inhib-... 

Suh YJ, Yoon SH, Sampson AP, et al Specific immunoglobulin E for staphylococcal enterotoxins in nasal polyps from patients with aspirin-intolerant asthma. Clin Exp Allergy 2004 34 1270-1275. Perez-Novo CA, Watelet JB, Claeys C, van Cauwenberge P, Bachert C Prostaglandin, leukotriene, and lipoxin balance in chronic rhinosinusitis with and without nasal polyposis. J Allergy Clin Immunol 2005 115 1189-1196. 

Smith, W.L. and Garcia-Perez, A. (1980). A two-receptor model for the mechanism of action of prostaglandins in the renal collecting tubule. In Bailey, J.M. (ed.) Prostaglandins, Leukotrienes, and Lipoxins, pp. 35-45. (New York and London Plenum Press)... 

Eicosanoids are formed from 20-carbon polyunsaturated fatty acids and make up an important group of physiologically and pharmacologically active compounds known as prostaglandins, thromboxanes, leukotrienes, and lipoxins. 

Rats fed a purified nonlipid diet containing vitamins A and D exhibit a reduced growth rate and reproductive deficiency which may be cured by the addition of linoleic, a-linolenic, and arachidonic acids to the diet. These fatty acids are found in high concentrations in vegetable oils (Table 14-2) and in small amounts in animal carcasses. These essential fatty acids are required for prostaglandin, thromboxane, leukotriene, and lipoxin formation (see below), and they also have various other functions which are less well defined. Essential fatty acids are found in the stmctural lipids of the cell, often in the 2 position of phospholipids, and are concerned with the structural integrity of the mitochondrial membrane. 

Hormonal lipids. We have already considered a number of hormones that are not water-soluble but may have to be transported by carrier proteins to their sites of action. These include retinoic acid (Box 22-A), metabolites of vitamin D (Box 22-C), and the plateletactivating factor (Box 8-A). The last functions in the brain311 as well as in blood. Hormonal lipids also include the prostaglandins (Fig. 21-7), leukotrienes, and lipoxins (Fig. 21-8). These are products of the eicosenoid cascade or network, which is activated by receptors linked to phospholipase C (Fig. 11-9). Cera-mide formed by hydrolysis of sphingomyelin initiates... 

Sun Y.-P., Tjonahen E., Keledjian R., Zhu M., Yang R., Recchiuti A., Pillai P. S., Petasis N. A., Serhan C. N. 2009. Anti-inflammatory and pro-resolving properties of benzo-lipoxin A4 analogs. Prostaglandins. Leukotrienes and Essential Fatty Acids. 81(5-6) 357-366. 

Eicosanoids These compounds, derived from eicosa- (20-carbon) polyenoic fatty acids, comprise the prostanoids, leukotrienes (LTs), and lipoxins (LXs). Prostanoids include prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (TXs). 

Figure 23-5. The three groups of eicosanoids and their biosynthetic origins. (PG, prostaglandin PGI, prostacyclin TX, thromboxane LT, leukotriene LX, lipoxin , cyclooxygenase pathway , lipoxygenase pathway.) The subscript denotes the total number of double bonds in the molecule and the series to which the compound...

Eicosanoid synthesis. Arachidonic acid is converted by cyclooxygenases into prostaglandins, and thromboxanes. Lipoxygenases convert arachidonic acid into HPETEs, which are then converted to lipoxins, leukotrienes, and 12-HETE (hydroxyeicosatetraenoic acid). Epoxygenases convert arachidonic acid into epoxides. 

Musser, J.H., Kreft, A., Kubrak, D., Banker, A., Failli, A., Steffan, R., Demerson, C., Nelson, J., Shah, U., Marshall, L., Sturm, R., Carlson, R., Berkenkopf, J., Grimes, D., Weichman, B. and Chang, J. (1991) Presented at the Xlth Washington International Spring Symposium (Prostaglandins, Leukotrienes, Lipoxins and PAF), Washington DC Abstr. 335. 

Wong, A., Hwang, S.M., Kreft, A. and Marshall, L. (1991) Presented at the Xlth Washington International Spring Symposium (Prostaglandins, Leukotrienes, Lipoxins and PAF), Washington DC Abstr. 307. 

The autacoids comprise histamine, serotonin, angiotensin, neurotensin, NO (nitric oxide), kinins, platelet-activating factor, endothelins and the four families of traditional eicosanoids - the leukotrienes and three types of prostanoids i.e. prostaglandins, prostacyclins, and thromboxanes. Several other natural occurring molecules are sometimes called eicos-anoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epoxyeicosatrienoic acids (EETs) and some endocannabinoids. However, not... 

The EFA are the precursors of the eicosanoids, namely prostaglandins, leukotrienes, thromboxanes, hydroxy fatty acids, and lipoxins. These important extracellular mediators at low concentrations have critical roles in skin homeostasis. At high concentrations they are involved... 

The EFA stored in the phospholipids of cell membranes are released by phospholipases, and then undergo oxidative transformation by the cyclooxygenase (COX) pathway to prostanoids and by the lipoxygenase pathway to hydroxy fatty acids and leukotrienes. The metabolism to prostanoids is catalyzed by two isoenzymes of COX, a constitutive (COX-1) and an inducible form (COX-2). The main products of COX metabolism of AA are prostaglandin E2 (PGE2), PGI A, and PGD2. In addition, A A is converted via 15-lipoxygenase to 15-hydroxyeicosatetraenoic acid (15-HETE) and lipoxins, by... 

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