Leukotriene Biosynthesis

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Leukotrienes are fatty acids and members of a larger group of biomolecules known as eicosanoids, which also encompasses cyclooxygenase products such as prostaglandins, thromboxanes, and prostacyclin and the products of 12- or 15-lipoxygenase (the lipoxins) and 5- and 15-lipoxygenase (5,6). Leu-kotrienes are synthesized in mast cells, eosinophils, and alveolar macrophages (7-9), all of which have been implicated as critical effector cells in the pathobiology of asthma. Airway epithelial cells (10,11) and pulmonary vascular endothelial cells (12) may also produce leukotrienes via trans-cellular metabolism (13,14). Leukotriene synthesis is initiated following trauma, infection, inflammation, and a variety of stimuli, including the activation of mast cell antigen-specific IgE bound to Fc receptors (15,16); hyperventilation of cold, dry air (17); aspirin ingestion by aspirin-intolerant individuals (18-20); hypoxia (21); hyperoxia (22); and exposure to platelet-activating factor (23). In these circumstances, cytosolic phospholipase A2 selectively cleaves arachidonic acid from perinuclear cell membranes, which is converted sequentially to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and then to leukotriene A4 (LTA4) (5,6-oxido-7,9-trans 11,

14-cis-eicosatetraenoic acid) by a catalytic complex consisting of 5-LO and the 5-LO activating protein (FLAP), which binds arachidonic acid and is critical to leukotriene synthesis (24) (Fig. 1). LTA4 is unstable and may be transformed through the action of the enzyme LTA4 epoxide hydrolase in polymorphonuclear leukocytes into LTB4, which is involved in eosino-phil and neutrophil chemotaxis. Alternatively, in the presence of LTC4 synthase, glutathione is adducted to the C6 position of LTA4 in eosinophils, mast cells, and alveolar macrophages to yield the molecule known as leukotriene C4 (LTC4). The glutamic acid moiety of LTC4 is cleaved by g-glutamyltranspeptidase to form the active entity leukotriene D4 (LTD4) whose glycine moiety may be cleaved by a variety of dipeptidases, resulting in the formation of leukotriene E4 (LTE4). LTC4, LTD4, and LTE4 are all known as the cysteinyl leukotrienes, as each one contains a cysteine.

Leukotrienes exert their biologic activities by binding to specific receptors that have been characterized functionally through comparisons of the activity of various agonists and antagonists. While leukotriene B4 (LTB4) binds to the B-leukotriene receptor (BLT), a G-protein-coupled

S-LO inhibitors (zileuton)

Leukotriene Biosynthesis Pathway

Arachidonic Acid

5-LlP0XyC6N«S6

FLAP Inhibitors

LTB4 antagonists

8-LT

S-HPETE

m Biosynthetic Pathways

(!□ Ligand-Receptor Interactions

B Points of Intervention by LT Modifiers

□ Effects of Activated LT Receptors

Mucus secretion X \ Bronchoconstriction Edema Eosinophilic

CysLT,

Figure 1 Leukotriene biosynthesis, effects, and points of therapeutic interruption. Leukotrienes are synthesized from arachidonic acid via the action of 5-LO and FLAP and help mediate airway inflammation. Leukotriene modifiers include both 5-LO inhibitors and cysteinyl leukotriene antagonists. FLAP inhibitors and LTB4 antagonists are currently under investigation. Source: Adapted from Ref. 196.

Cysteinyl-LT antagonists (LTRAs)

zafirlukast montelukast pranlukast

Mucus secretion X \ Bronchoconstriction Edema Eosinophilic

CysLT,

Figure 1 Leukotriene biosynthesis, effects, and points of therapeutic interruption. Leukotrienes are synthesized from arachidonic acid via the action of 5-LO and FLAP and help mediate airway inflammation. Leukotriene modifiers include both 5-LO inhibitors and cysteinyl leukotriene antagonists. FLAP inhibitors and LTB4 antagonists are currently under investigation. Source: Adapted from Ref. 196.

receptor cell surface protein that predominantly transduces chemotaxis and cellular activation (25-28), the cysteinyl leukotrienes bind to two distinct receptors that have been identified pharmacologically as CysLT1 and CysLT2. Previously known as the LTD4 receptor LTRD, CysLT1 is a 45-kDa membrane protein found in airway smooth muscle. Stimulation of this receptor by phosphoinositide-stimulated signal transduction causes smooth muscle constriction (29-32). LTD4 is the preferred ligand, but LTC4 and LTE4 also bind to this receptor, albeit with less biopotency (33-36). The CysLT2 receptor was previously known as the LTC4 receptor or LTRc. Stimulation of this pulmonary vascular smooth muscle receptor results in smooth muscle constriction and chemotaxis.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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