Current state and future prospect of the therapeutic strategy targeting cysteinyl leukotriene metabolism in asthma

Abstract

Asthma is an allergic disorder with dominant type 2 airway inflammation, and its prevalence is increasing worldwide. Inhalation of corticosteroids is the primary treatment for asthma along with add-on drugs, including long-acting β2 agonists and/or cysteinyl leukotriene (cys-LT) receptor antagonists, in patients with poorly controlled asthma. Cys-LTs are composed of leukotriene C4 (LTC₄), LTD₄, and LTE₄, which are enzymatically metabolized from arachidonic acid. These molecules act as inflammatory mediators through different types of high-affinity receptors, namely, CysLT₁, CysLT₂, and CysLT₃ (also named as GPR99). CysLT₁ antagonists possessing anti-inflammatory and bronchodilatory effects can be orally administered to patients with asthma. Recently, molecular biology-based studies have revealed the mechanism of inflammatory responses via other receptors, such as CysLT₂ and CysLT₃, as well as the importance of upstream inflammatory regulators, including type 2 cytokines (e.g., interleukins 4 and 5), in controlling cys-LT metabolism. These findings indicate the therapeutic potential of pharmacological agents targeting cys-LT metabolism-related receptors and enzymes, and antibody drugs neutralizing or antagonizing type 2 cytokines. This review focuses on the current state and future prospect of the therapeutic strategy targeting cys-LT metabolism.

Keywords: Antibodies; Asthma; Cysteinyl leukotrienes; Leukotriene receptor antagonist; Type 2 cytokines.