Targeting Cysteinyl Leukotrienes in Patients with Rhinitis, Sinusitis and Paranasal Polyps
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Am J Respir Med 2002; 1 (6): 403-408 1175-6365/02/0006-0403/$25.00/0 © Adis International Limited. All rights reserved.
Targeting Cysteinyl Leukotrienes in Patients with Rhinitis, Sinusitis and Paranasal Polyps Steven M. Parnes Department of Surgery, Division of Otolaryngology, Albany Medical College, Albany, New York, USA
Abstract
Leukotrienes have been known in the field of immunology since the 1930s. At that time they were referred to as the slow reacting substance of anaphylaxis. They were not, however, characterized until the 1980s, when they were noted to be formed during the breakdown of arachidonic acid by the enzyme 5-lipoxygenase. The leukotrienes consist of leukotriene (LT) A 4, LTB4, LTC4, LTD4 and LTE4, so named because the molecule was originally isolated from leukocytes and therefore its carbon backbone contains three double bonds in series, which constitutes a trion. This structural information provided the key to the oxidative pathway of lipometabolism, known as the 5-lipoxygenase. Leukotrienes are classified as inflammatory mediators, and therefore they are produced by a number of cell types, particularly mast cells, eosinophils, basophils, macrophages and monocytes. With the identification of asthma, allergic rhinitis and paranasal sinusitis associated with inflammatory pathways, the leukotrienes have been implicated in the pathogenesis of these conditions and have become targets for therapeutic modulation. Leukotriene synthesis inhibitors have been used successfully in the treatment of patients with asthma where they have demonstrated the ability to induce bronchial dilatation, provide protection against bronchoprovocation tests and significantly diminish symptoms. When it was serendipitously noted that patients who had concomitant nasal pathology also showed improvement, leukotriene synthesis inhibitors were used as adjuvant therapy in the management of patients with rhinitis, sinusitis and nasal polyposis. Preliminary studies have demonstrated improvements in nasal airflow and reduced recurrence of nasal polyps as noted by endoscopy and imaging studies. Leukotriene synthesis inhibitors therefore appear to be a novel treatment modality for patients with rhinitis, sinusitis and nasal polyps when used as adjunctive therapy.
1. The Lipoxygenase Pathway The synthesis of leukotrienes begins with the cleavage of arachidonic acid from the cell membranes via the action of phospholipase A2. Intracellularly, arachidonic acid is then converted sequentially to 5,hydroperoxyeicosatetraenoic acid and then to leukotriene (LT) A4 by 5-lipoxygenase and 5-lipoxygenase activating protein. LTA4 is then converted to LTC4 by its synthase, and transported into the extracellular micro-environment where it is converted to LTD4 by the action of γ-glutanyltranspeptidase. A variety of dipeptidases subsequently convert LTD4 to the last member of the chain, LTE4 (figure 1). LTC4, LTD4 and LTE4 all contain cysteine, and therefore are collectively known as the cysteinyl leukotrienes, originally known as the slow reactive
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