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Agents affecting the 5-lipoxygenase pathway in the treatment of asthma

Author
Marc Peters-Golden, MD
Section Editors
Robert A Wood, MD
Bruce S Bochner, MD
Deputy Editor
Helen Hollingsworth, MD

INTRODUCTION

The 5-lipoxygenase (5-LO) pathway is a series of biochemical reactions in which arachidonic acid, a component of membrane phospholipids, is transformed into pro-inflammatory mediators called leukotrienes [1,2]. Leukotrienes possess diverse biological actions and are increasingly implicated in a variety of disease states [3,4].

Several lines of evidence support the role of leukotrienes in the pathogenesis of asthma, and agents with the capacity to inhibit the synthesis or action of leukotrienes are used in the treatment of asthma. Such agents represent the first new class of asthma medications to be introduced since inhaled glucocorticoids (inhaled GC), and the first to target a specific type of mediator.

This topic reviews the evidence for the involvement of leukotrienes in asthma and the use of anti-leukotriene agents in the management of asthma. Recommendations for the treatment of asthma, incorporating the use of these and other therapies, are reviewed separately. (See "An overview of asthma management".)

LEUKOTRIENE SYNTHESIS AND BIOLOGY

To understand the mechanisms of action of the anti-leukotriene agents, it is helpful to review briefly leukotriene synthesis and biology. Leukotrienes are synthesized within various types of leukocytes in response to activation of these cells. Upon activation, intracellular calcium concentrations rise, causing the enzyme 5-LO to translocate from soluble cytosolic or intranuclear pools to the perinuclear membrane. Here, it associates with the helper protein, 5-LO activating protein (FLAP) (figure 1) [5].

FLAP is thought to "present" substrate arachidonate derived from membrane phospholipids to 5-LO, permitting it to catalyze the formation of an unstable intermediate known as leukotriene A4 (LTA4). This intermediate can then be transformed into two different classes of leukotrienes, cysteinyl leukotrienes (cysLTs) and leukotriene B4 (LTB4).

                               

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Literature review current through: Nov 2016. | This topic last updated: Fri Oct 16 00:00:00 GMT+00:00 2015.
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