Physiological action of leukotrienes

Leukotrienes have potent biological activity. A summary of some of their more important actions is provided in Table 2.15. The peptidoleukotrienes contract respiratory, vascular and intestinal smooth muscles. In general LTC4 and LTD4 are more potent than LTE4. By contrast, LTB4 is a chemotactic agent for neutrophils and eosinophils. Although it can cause plasma exudation by increasing vascular permeability, it is less potent than the peptidoleu-kotrienes. These actions of the leukotrienes have implications for asthma, immediate hypersensitiv-ity reactions, inflammatory reactions and myo-cardial infarction.

The action of leukotrienes at the molecular level first of all involves binding to specific high-affinity receptors. Receptors for LTB4, LTC4, D4 and E4 have been characterized. The detailed mechanism has been studied best in neutrophils where binding of LTB4 involves a G-protein sensitive to pertussis toxin. An inositol lipid-specific phospholipase C (Sections 7.2.4 and 7.9) is then activated and intracellular Ca2+ is elevated both by increased influx and by release from stores.

The function of the 12- and 15-lipoxygenases is much less clear than that of the 5-lipoxygenase. Nevertheless, it is thought that the 15-lipoxygenase products (15-HETE) may play a role in endocrine (e.g. testosterone) secretion. A build-up of 12-HETE

Fig. 2.46 A model for the synthesis and release of leukotriene LTC4. FLAP and LTC4 synthase are shown as integral nuclear membrane proteins, with a phospholipase (PL) associating with this membrane to release AA®. Following the release of AA, 5-LOX (5-LO) translocates to the nuclear membrane® in a process regulated by FLAP®. 5-LOX then converts AA into LTA4, which is subsequently converted into LTC4 by LTC4 synthase®. LTC4 is exported from the cell by a membrane carrier®. Points at which this process can be inhibited are indicated (1-5; blockade of PL, FLAP, 5-LOX, LTC4 synthase and the carrier protein, respectively). Reproduced from Vickers (1998) with kind permission of the author and Portland Press.

Fig. 2.46 A model for the synthesis and release of leukotriene LTC4. FLAP and LTC4 synthase are shown as integral nuclear membrane proteins, with a phospholipase (PL) associating with this membrane to release AA®. Following the release of AA, 5-LOX (5-LO) translocates to the nuclear membrane® in a process regulated by FLAP®. 5-LOX then converts AA into LTA4, which is subsequently converted into LTC4 by LTC4 synthase®. LTC4 is exported from the cell by a membrane carrier®. Points at which this process can be inhibited are indicated (1-5; blockade of PL, FLAP, 5-LOX, LTC4 synthase and the carrier protein, respectively). Reproduced from Vickers (1998) with kind permission of the author and Portland Press.

(46 x normal) has been reported in lesions of patients suffering from the skin disease psoriasis. This compound is know to be a chemoattractant and topical application of 12-HETE causes erythema (similar to sunburn). Interestingly, one of the most effective anti-erythema treatments is etretinate, which inhibits the 12-lipoxygenase. Etretinate has been used for psoriatic patients, but it is particularly effective for anti-sunburn treatment.

Table 2.15 Biological effects of leukotrienes

Effect

Comments

Respiratory Peptidoleukotrienes cause constriction of bronchi especially smaller airways and increase mucus secretion

Microvascular Peptidoleukotrienes cause arteriolar constriction, venous dilation, plasma exudation

Leukocytes LTB4 chemotactic agent for neutrophils, eosinophils, e.g. increase degranulation of platelets, cell-surface receptors and adherence of polymorphonucleocytes to receptor cells

Gastrointestinal Peptidoleukotrienes cause contraction of smooth muscle (LTB4 no effect)

2.4.9 For eicosanoid synthesis an unesterified fatty acid is needed

A necessary prerequisite for eicosanoid formation is the availability of an appropriate unesterified fatty acid. In animals, this is most commonly ara-chidonic acid, which is the dominant poly-unsaturated fatty acid in most membrane phospholipids. The concentration of unesterified arachidonic acid in cells is well below the Km for prostaglandin H synthetase. Thus, the first stage for eicosanoid formation will normally be an activation of the release of arachidonate from position 2 of phosphoglycerides that contain it. Two classes of phospholipids are thought to play major roles as sources of arachidonate in cells: phosphatidylcholine (the major membrane constituent) and the phosphoinositides (by virtue of the high enrichment of arachidonate at position 2). Thus, hydrolysis of phosphoinositides not only produces two second messengers directly (Section 7.9) but may also initiate an arachidonate cascade. Other potential sources of arachidonic acid are the plasmalogens (Section 6.2.5) that also have a high enrichment at the sn-2 (acyl) position. Because plasmalogens are poor substrates for phospholi-pase A2, they are hydrolysed by a plasmalogenase first. Thus, release of arachidonic acid from plasmalogens could be controlled independently from that for diacylphosphoglycerides.

Two main types of stimuli increase arachidonate release. These can be called physiological (specific) and pathological (non-specific). Physiological stimuli, such as adrenaline, angiotensin II and certain antibody-antigen complexes, cause the selective release of arachidonic acid. In contrast, pathological stimuli, such as mellitin or tumour promoters like phorbol esters, have generalized effects on cellular membranes and promote release of all fatty acids from position 2 of phosphoglycerides.

Of the various cellular lipases stimulated by hormones or other effectors and which, in theory, could give rise to arachidonate hydrolysis, cytosolic phospholipase A2 and the non-pancreatic secretory phospholipase A2 are the most important. Cytosolic phospholipase A2 is stimulated by Ca2+ and hormonal-induced mobilization of Ca2+ leads to movement of the enzyme from the cytosol to the ER and nuclear envelope. It is relatively specific for arachidonate and is stimulated by phosphorylation.

Secretory phospholipase A2 is also stimulated by Ca2+, but at the higher concentrations found outside the cell. It is relatively non-specific towards different phospholipids and towards the fatty acid at the sn-2 position. Its involvement in pros-taglandin synthesis has been shown in endothelial cells by the use of antibodies that prevent it binding to the cell surface. It has been suggested that cyto-solic phospholipase A2 produces the initial burst of prostaglandin synthesis whereas the secretory enzyme is involved in late-phase prostaglandin formation after cells have been stimulated further by cytokines, inflammatory mediators or growth factors.

It is also of interest that phospholipase A2, the activity of which is needed to initiate eicosanoid production, is also needed to produce another type of biologically active lipid: platelet activating factor (Section 7.1.10).

2.4.10 Essential fatty acid activity is related to double bond structure and to the ability of such acids to be converted into a physiologically active eicosanoid

Work from the Dutch school and from Holman's laboratory at the Hormel Institute, Minnesota, originally showed that only those fatty acids (including new synthetic odd-numbered acids) that act as precursors for biologically active eicosanoids have essential fatty acid (EFA) activity. This and other results superseded the old dogma that essential fatty acids all had the n-6, n-9 double bond system. Indeed, some synthetic acids without this structure had EFA activity (Table 2.16). Van Dorp and his colleagues at the Unilever Laboratories at Vlaar-dingen have made the postulate that only those fatty acids capable of being converted into the A5,8,11,14-tetraenoic fatty acids of chain lengths 19C, 20C and 22C will show EFA activity because only these tetraenoic acids can give rise to physiologically active eicosanoids. However, it is now known that columbinic acid (trans-5, cis-9, cis-12-18:3), when given to EFA-deficient rats, normalizes growth and cures the dermatitis yet it is unable to form an eicosanoid.

Moreover, although there is a correlation between EFA activity and the potential to be converted to eicosanoids, one cannot cure EFA deficiency by infusion of eicosanoids because they are rapidly destroyed and because different cells produce their own special pattern of eicosanoids. However, one of the first organs to show EFA deficiency is the skin, whose water permeability is very much increased in this condition. Topical application of EFA to skin can reverse the deficiency symptoms and there is now evidence that topical application of prostaglandins can also be very effective. (See Sections 4.2.3.4 and 6.6.6 for other comments about lipids and skin diseases.)

We are still a long way from being able to account for the fate of all the EFA that enter the body and the fate of the eicosanoids that may be formed from them. Eicosanoids are metabolized very rapidly and their metabolites excreted in the urine or bile. The detection, isolation and analysis of such metabolites is, therefore, one approach to studying the daily eicosanoid production. In this way it has been estimated that 1 mg of prostaglandin metabolites is formed in 24 h in man - considerably less than the 10 g of EFA, which are thought to be necessary daily. However, the demonstration that EFA like linoleic acid may have additional functions (Sec

Table 2.16 Relationship between fatty acid structure and EFA activity

Position of double bonds

Fatty acid chain length From carboxyl end (A) From methyl end (ra) EFA potency (unit g 1)

18:2

9, 12

6, 9

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