Inhibitory Effects of Lodoxamide on Eosinophil Activation

Abstract

Recent reports describe the beneficial use of lodoxamide, an anti-allergic compound, for the treatment of asthma and allergic conjunctivitis. Lodoxamide is known as a mast cell stabilizer, however, the association of a significant clinical improvement with a specific decrease in eosinophil infiltrate suggested possible direct effects of lodoxamide on eosinophils. The chemotactic response of eosinophils to fMLP as well as to IL-5, in vitro, was very significantly and dose-dependently inhibited by Lodoxamide. Lodoxamide was also able to strongly inhibit the release of eosinophil peroxidase after IgA-dependent activation and, to a lesser extent, the release of eosinophil cationic protein and eosinophil-derived neurotoxin. Moreover, the release of cytotoxic mediators evaluated in an antibody-dependent cytotoxicity assay against parasitic targets was also significantly reduced, not only in the case of human eosinophils but also in a rat eosinophil-mast cell model of cytotoxicity. Taken together, these results indicate that lodoxamide can exert potent inhibitory effects on eosinophil activation in vitro combined with a strong inhibition of eosinophil attraction, leading therefore to a reduction in their pathological potential in vivo.

Invited Lecture: Role of Membrane Receptors in the Release of T Helper 1 and 2 Cytokines by Eosinophils

“…After the demonstration that drugs like lodoxamide, a potent antiallergic drug, could inhibit several parameters of eosinophil activation including chemotaxis and release of cytotoxic mediators [22], we have recently extended this observation to a new immunosuppressive drug, suplatast tosilate (IPD), shown to specifically inhibit the Th2 immune response [23]. …”

Inhibitory effects of ketotifen on eotaxin‐dependent activation of eosinophils: consequences for allergic eye diseases

“…Inhibiting the inflammatory influx of eosinophils and/or the release of toxic mediators would allow significant treatment of allergic inflammation. Our previous in vitro studies have shown the usefulness of anti‐allergic drugs by demonstrating that molecules, such as cetirizine or lodoxamide, could have a direct effect on eosinophil functions, allowing better understanding of the drug mechanism (6, 29). In this study, we investigated the effect of ketotifen, a drug with anti‐anaphylactic and antihistaminic properties already used in the treatment of asthma and AC, on eosinophil chemoattraction and on the release of inflammatory mediators, such as ROS, ECP, and EDN by activated eosinophils.…”

“…The measurement of leukocyte chemotaxis was assessed by a modification of the Boyden micropore filter technique, as previously described (6). Briefly, the assay is carried out in a 48‐well microchemotaxis assembly (Neuroprobe; Cabin John, MD).…”

“…The migration of eosinophils from the blood to the tissues is controlled by membrane adhesion molecules and by soluble factors including various cytokines and chemokines, as well as small molecular weight substances (5). Among these, formyl‐methionine‐leucine‐phenylalanine (fMLP), interleukin (IL)‐5 and eotaxin have been shown to exert potent chemotactic activity on eosinophils in vitro (6). Increased levels of IL‐5 have been found in tears of VKC patients (7), suggesting its potential role in eosinophil recruitment.…”

Mechanisms of Antihistamines and Mast Cell Stabilizers in Ocular Allergic Inflammation

“…Lodoxamide was shown to downregulate ICAM-1 expression (both constitutive and IFNγ -stimulated) in a conjunctival epithelial cell line [56]. Capron and coworkers demonstrated in vitro that lodoxomide significantly and dose-dependently inhibited the chemotactic response of human eosinophils to N-formyl methionine leucylphenylalanine (fMLP) and IL-5 [58]. Lodoxamide also inhibited IgA dependent release of eosinophil peroxidase (EPO), eosinophil cationic protein (ECP) and eosinophilderived neurotoxin (EDN).…”