Curr Allergy Asthma Rep (2015) 15:64 DOI 10.1007/s11882-015-0564-7 RHINOSINUSITIS (J MULLOL, SECTION EDITOR) Antileukotrienes in Upper Airway Inflammatory Diseases Cemal Cingi1,5 & Nuray Bayar Muluk2 & Kagan Ipci3 & Ethem Şahin4 # Springer Science+Business Media New York 2015 Abstract Leukotrienes (LTs) are a family of inflammatory zileuton, ZD2138, Bay X 1005, and MK-0591). CysLTs have mediators including LTA4,LTB4,LTC4,LTD4, and LTE4. important proinflammatory and profibrotic effects that con- By competitive binding to the cysteinyl LT1 (CysLT1)recep- tribute to the extensive hyperplastic rhinosinusitis and nasal tor, LT receptor antagonist drugs, such as montelukast, polyposis (NP) that characterise these disorders. Patients who zafirlukast, and pranlukast, block the effects of CysLTs, im- receive zafirlukast or zileuton tend to show objective improve- proving the symptoms of some chronic respiratory diseases, ments in, or at least stabilisation of, NP.Montelukast treatment particularly bronchial asthma and allergic rhinitis. We may lead to clinical subjective improvement in NP. reviewed the efficacy of antileukotrienes in upper airway in- Montelukast treatment after sinus surgery can lead to a signif- flammatory diseases. An update on the use of antileukotrienes icant reduction in eosinophilic cationic protein levels in se- in upper airway diseases in children and adults is presented rum, with a beneficial effect on nasal and pulmonary symp- with a detailed literature survey. Data on LTs, antileukotrienes, toms and less impact in NP. Combined inhaled corticosteroids and antileukotrienes in chronic rhinosinusitis and nasal and long-acting β-agonists treatments are most effective for polyps, asthma, and allergic rhinitis are presented. preventing exacerbations among paediatric asthma patients. Antileukotriene drugs are classified into two groups: CysLT Treatments with medium- or high-dose inhaled corticoste- receptor antagonists (zafirlukast, pranlukast, and montelukast) roids, combined inhaled corticosteroids and LT receptor an- and LT synthesis inhibitors (5-lipoxygenase inhibitors such as tagonists, and low-dose inhaled corticosteroids have been re- ported to be equally effective. Antileukotrienes have also been This article is part of the Topical Collection on Rhinosinusitis reported to be effective for allergic rhinitis. * Cemal Cingi [email protected] Keywords Leukotrienes . Antileukotriene drugs . Asthma . Nuray Bayar Muluk Chronic rhinosinusitis with nasal polyposis Allergic rhinitis [email protected] Kagan Ipci [email protected] Introduction Ethem Şahin [email protected] Leukotrienes (LTs) are inflammatory mediators, previously 1 Department for ORL Head and Neck Surgery, Faculty of Medicine, known as slow-reacting substances of anaphylaxis, produced Eskişehir Osmangazi University, Eskisehir, Turkey by a number of cell types, including mast cells, eosinophils, 2 Department for ORL Head and Neck Surgery, Faculty of Medicine, basophils, macrophages, and monocytes [1]. LTs are synthe- Kırıkkale University, Kırıkkale, Turkey sised from arachidonic acid (AA) by the 5-lipoxygenase (5- 3 ENT Department, Ankara Koru Hospital, Ankara, Turkey LO) pathway [2, 3] (Fig. 1). Synthesis of these mediators 4 ENT Clinics, Bayındır Içerenköy Hospital, Istanbul, Turkey results from the cleavage of AA in cell membranes. LTs exert 5 ENT Department, Eskisehir Osmangazi University, their biologic effects by binding to and activating specific Eskisehir, Turkey adaptors. This occurs in a series of events, leading to the 64 Page 2 of 11 Curr Allergy Asthma Rep (2015) 15:64 Fig. 1 Synthesis of leukotrienes from arachidonic acid. Adapted from reference 3 contraction of human airway smooth muscle, cell chemotaxis, airway remodelling by increasing the deposition of collagen and increased vascular permeability [1]. below the basement membrane, enhancing collagen synthesis The LT family consists of LTA4,LTB4,LTC4,LTD4,and and degradation by fibroblasts, and promoting the prolifera- LTE4 [4••, 5]. An unstable intermediate product, LTA4,is tion of bronchial epithelial cells and smooth muscle cells. LT formed and successively converted into LTC4,LTD4,and modifiers can reduce cytokine expression by blocking their LTE4. A separate pathway produces LTB4.LTC4 is actions. The reverse phenomenon is also true: cytokines can metabolised enzymatically into LTD4 and subsequently into modulate LT expression [5]. LTE4, which is excreted in the urine. Several cells such as LTs act by binding to specific receptors of the rhodopsin mast cells, basophils, eosinophils, monocytes/macrophages, class that are located on the outer plasma membrane of struc- dendritic cells, and T lymphocytes can produce LTs in re- tural and inflammatory cells [3]. Once ligated by the LT, these sponse to receptor-activated, antigen-antibody interactions receptors interact with G proteins in the cytoplasm, thereby [2]. By competitive binding to the CysLT1 receptor, LT eliciting an increase in intracellular calcium and a reduction in receptor antagonist (LTRA) drugs, such as montelukast, intracellular cyclic AMP. These proximal signals activate zafirlukast, and pranlukast, block the effects of cysteinyl downstream kinase cascades in ways that alter various cellular LTs (CysLTs), improving the symptoms of some chronic activities, ranging from motility to transcriptional activation respiratory diseases, particularly bronchial asthma and [6]. In the bronchi of aspirin-intolerant asthma (AIA) patients, allergic rhinitis [4••, 5]. whose asthma is characterised by increased production of CysLTs are potent proinflammatory mediators produced CysLTs, there is overexpression of LTC4 synthase. This phe- from AA through the 5-LO pathway. They have important nomenon is explained, at least in part, by a genetic polymor- pharmacological effects by interacting with at least two differ- phism of the LTC4 synthase gene. A common promoter vari- ent receptors: CysLT1 and CysLT2.CysLT1 mediates ant of the gene creates a predisposition to AIA by reinforcing sustained bronchoconstriction, mucus secretion, and oedema the effector mechanism of bronchoconstriction. Aspirin chal- in the airways. Selective antagonists of CysLT1 approved for lenge studies, coupled with the estimation of LTC4 synthase the treatment of asthma block the proasthmatic effects of polymorphism and LTC4 urinary excretion, point to some het- CysLT1. Experiments in mice that are deficient in CysLT2, erogeneity among patients with AIA [3, 7]. or that overexpress CysLT2 in the lungs, have indicated that In this review paper, we present the efficacy of CysLT2 does not mediate bronchoconstriction but rather con- antileukotrienes in upper airway inflammatory diseases. tributes to inflammation, vascular permeability, and tissue fi- brosis [4••]. The two classes of LTs, LTB4 and peptidylcysteinyl LTs, Antileukotrienes also have important mediator functions in the upper airways. They promote inflammatory cell recruitment and activation During the early-phase response to antigens, CysLTs are re- (primarily of eosinophils) as well as fibrosis and airway re- leased by mast cells and basophils; however, in the late phase, modelling, with actions such as smooth muscle and epithelial they are synthesised by eosinophils and macrophages [8]. cell proliferation. The CysLTs increase the expression of ad- CysLTs cause contraction of bronchial smooth muscles, mu- hesion molecules such as P selectin. They also promote cous production, oedema, and increased vascular Curr Allergy Asthma Rep (2015) 15:64 Page 3 of 11 64 permeability. LTD4 challenge in humans causes an increase in two well-characterised receptors (CysLT1 and CysLT2) and nasal mucosal blood flow and airway resistance [9]. newly described selective LTE4 receptors [18–21]. Antileukotriene drugs are classified into two groups based Chronic hypereosinophilic rhinosinusitis (CHES) is an in- on their mechanism of action: LTRAs (zafirlukast, pranlukast, flammatory disease characterised by the prominent accumula- montelukast), which block the LT receptor and thus block the tion of eosinophils in the sinuses and, when present, associat- end-organ response of LTs; and LT synthesis inhibitors ed with nasal polyps [21–24]. While NPs frequently occur (zileuton, ZD2138, Bay X 1005, MK-0591), which block with CF, AFS, and AERD, in the absence of one of these the biosynthesis of cysteinyl LTs and LTB4 [1]. conditions, the presence of NP (particularly in the concomi- Zafirlukast is an LTD4 receptor antagonist that has been tant presence of asthma) has been proposed as presumptive used for LTD4-induced bronchoconstriction, exercise chal- evidence for CHES [25, 26]. In CHES, the sinus tissue dem- lenge, cold-induced asthma, and chronic asthma. LT synthesis onstrates a marked increase in cells that express cytokines inhibitors block the biosynthesis of cysteinyl LTs. Zileuton is a (e.g., IL-5 and GM-CSF), chemokines (e.g., CCL5,CCL11, 5-lipoxygenase inhibitor that has been used in exercise, cold, and CCL24), and proinflammatory lipid mediators (e.g., and aspirin-induced bronchial hyperresponsiveness. LT mod- CysLTs) that are responsible for the differentiation, survival, ifiers represent the first mediator-specific therapeutic option and activation of eosinophils [22, 27, 28]. for rhinitis and asthma [10, 11]. Antileukotrienes in chronic rhinosinusitis and nasal polyps The currently used antileukotriene drugs are described in are shown on Table 1. In Pérez-Novo et al.’s[29••] study, the succeeding