A Novel CC-Chemokine Receptor 3 Antagonist, Ki19003, Inhibits Airway Eosinophilia and Subepithelial/Peribronchial Fibrosis Induced by Repeated Antigen Challenge in Mice

Abstract

Abstract. CC-chemokine receptor 3 (CCR3) is a chemokine receptor for which major ligands, CC-chemokine ligand (CCL) 11, CCL24, and CCL26, are known to be involved in chemotaxis for eosinophils. In the present study, we evaluated the effect of a low molecular weight CCR3-receptor antagonist, Ki19003 (4-[[5-(2,4-dichlorobenzylureido)pentyl][1-(4-chlorophenyl)ethyl]amino]butanoic acid), on airway remodeling in a mouse model of allergic asthma. BALB/c mice were sensitized twice by intraperitoneal injection of ovalbumin (OA) and exposed daily to 1% OA for 3 weeks. Twenty-four hours after the final antigen challenge, bronchoalveolar lavage and histological examinations were carried out. Ki19003 clearly inhibited antigen-induced increase in the number of eosinophils in bronchoalveolar lavage fluid (BALF), but did not affect the number of other cell types examined in this study. Ki19003 also inhibited the increased production of transforming growth factor-β 1 in BALF and the amount of hydroxyproline in the lungs in a dose-dependent manner. Furthermore, Ki19003 significantly attenuated allergen-induced subepithelial and peribronchial fibrosis. These findings indicate that CCR3 antagonism prevents not only the infiltration of eosinophils into the airways but also the development of allergen-induced subepithelial and peribronchial fibrosis. Therefore, a CCR3 antagonist may be useful in the treatment of airway remodeling, especially subepithelial and peribronchial fibrosis, in allergic asthma.

The Biology of Eosinophils and Their Role in Asthma

“…The airways of patients with asthma have been shown to contain higher numbers of cells expressing mRNA for CCR3 and its ligands, compared to non-asthmatic control subjects (9). In mouse models of allergic airway inflammation, antigen-induced airway eosinophilia may be inhibited by the administration of either a monoclonal antibody against CCR3 (10) or a low molecular weight CCR3-antagonist (11). …”

Eosinophilic Gastroenteritis and Colitis: a Comprehensive Review

“…CCchemokine receptor 3 (CCR3) is an eotaxin receptor known to be involved in eosinophil chemotaxis. Komai et al reported that CCR3 antagonism not only prevents the infiltration of eosinophils into the airways but also prevents the development of allergen-induced subepithelial and peribronchial fibrosis in mouse models [139]. IL-4 and IL-13 are two cytokines produced by activated CD4 + T cells and are important in the development of allergic responses [140].…”

Regulation of Chemokine- Receptor Interactions and Functions

“…Heparin in various forms inhibits leukocyte recruitment to mouse models of arthritis, traumatic brain injury and lipopolysaccharide (LPS) treatment [106][107][108], although its effectiveness depends upon the dose given and the duration of inflammation [109]. These studies show potential role of GAG mimetics on chemokine-mediated immunomodulation when administered, either local or systemically, however it should be noted that administered heparin is likely to interact with all cytokines due to its highly negative charge, and a more chemokine-specific gradient disruption method could be more beneficial.…”