Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Review article Leukotriene D 4 role in allergic asthma pathogenesis from cellular and therapeutic perspectives Nosayba Al-Azzam a, ⁎ , Lina Elsalem b a Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, Jordan b Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Jordan ARTICLE INFO Keywords: Leukotriene D 4 Asthma Infammatory cells Structural cells CysLT 1 R CysLT 1 R antagonists ABSTRACT Asthma is a chronic infammatory and allergic disease that is mainly characterized by reversible airway ob- struction and bronchial hyperresponsiveness. The incidence of asthma is increasing with more than 350 million people worldwide are afected. Up to now, there is no therapeutic option for asthma and most of the prescribed drugs aim to ameliorate the symptoms of the disease especially during the acute exacerbations after trigger exposure. Asthma is a heterogonous disease that involves interactions between infammatory mediators and cellular components within the disease microenvironment including infammatory and structural cells. Cysteinyl leukotrienes (cys-LTs) are infammatory lipid mediators that have potent roles in asthma pathogenesis. CysLTs consisting of LTC 4 , LTD 4 , and LTE 4 are mainly secreted by leukocytes and act through three main G-protein coupled receptors (CysLT 1 R, CysLT 2 R, and CysLT 3 R). LTD 4 is the most potent bronchoconstrictor which gives it the priority to be discussed in detail in this review. LTD 4 binds with high afnity to CysLT 1 R and many studies showed that using CysLT 1 R antagonists such as montelukast has a benefcial efect for asthmatics especially in corticosteroid refractory cases. Since asthma is a heterogeneous infammatory disease of many cell types in- volved in the disease pathogenies and LTD 4 has a special role in infammation and bronchoconstriction, this review highlights the role of LTD 4 on each cellular component in asthma and the benefts of using CysLT 1 R antagonists in ameliorating LTD 4 -induced efects. 1. Introduction Asthma is an infammatory disease that is clinically characterized by airway obstruction and hyperresponsiveness. Asthma is a chronic dis- ease of the airways with acute exacerbations after the patient's exposure to certain factors such as allergens, viral infections, and irritants [1]. The disease incidence is increasing with more than 350 million people worldwide are afected [2,3]. Asthmatic airways have histopathologic changes that characterize the disease. The airway epithelial layer usually has shedding of ciliated columnar cells, goblet cells that secrete mucus, and squamous cell metaplasia. The subepithelial basement membrane has normal or increased thickness. The airways also have increased thickness and infltration of infammatory cells mainly of T lymphocytes, eosinophils, macrophages, and mast cells (MCs) [4]. Not only infammatory cells release infammatory mediators, but also structural cells of the airways, including epithelial cells, endothelial cells, fbroblasts, and airway smooth muscle cells, are also essential factories of infammatory and lipid mediators in asthma [5]. Asthma is recognized as a heterogeneous disease in which diferent infammatory and structural cells orchestrate the infammatory re- sponses [6]. Asthma is generally classifed as eosinophilic and non-eo- sinophilic subtypes depending on the abundance of eosinophils in the airway or peripheral blood. Approximately, 50% of patients fall into each group [7]. Eosinophils are key infammatory cells that play an important role in airway hyperresponsiveness, mucus production, and airway remodeling in allergic asthma [7,8]. Apart from eosinophils, MCs, dendritic cells (DCs), macrophages and Th2 lymphocytes [9], as well as neutrophils [10,11] play an important and specifc role in asthma pathogenesis. Endothelium integrity is also an important factor that if disturbed it allows the infammatory cells to transmigrate to the lung parenchyma causing tissue damage [12]. Structural cells in the airways, consisting of epithelial cells, fbroblasts, and smooth muscle cells are key efectors in asthma that secrete many infammatory mediators such as cytokines and lipid mediators. Other than secreting infammatory mediators, structural cells also play other roles in asthma pathogenesis for example epithelial cells act as a bridge that connects https://doi.org/10.1016/j.lfs.2020.118452 Received 11 August 2020; Received in revised form 10 September 2020; Accepted 12 September 2020 ⁎ Corresponding author at: Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, P.o. Box 3030, Irbid 22110, Jordan. E-mail address: nzalazzam@just.edu.jo (N. Al-Azzam). Life Sciences 260 (2020) 118452 Available online 18 September 2020 0024-3205/ © 2020 Elsevier Inc. All rights reserved. T