Different anti-remodeling effect of nilotinib and fluticasone in a chronic asthma model

• Published in: The Korean journal of internal medicine Vol. 31; no. 6; pp. 1150 - 1158
• Main Authors: Kang, Hye Seon, Rhee, Chin Kook, Lee, Hea Yon, Yoon, Hyoung Kyu, Kwon, Soon Seok, Lee, Sook Young
• Format: Journal Article
• Language: English
• Published: Korea (South) The Korean Association of Internal Medicine 01.11.2016; 대한내과학회
• Subjects: Administration, Intranasal; Airway Remodeling - drug effects; Animals; Anti-Inflammatory Agents - administration & dosage; Asthma - drug therapy; Asthma - metabolism; Asthma - pathology; Asthma - physiopathology; Bronchodilator Agents - administration & dosage; Cell Line; Cell Proliferation - drug effects; Chronic Disease; Collagen - metabolism; Cytokines - metabolism; Disease Models, Animal; Drug Therapy, Combination; Female; Fluticasone - administration & dosage; Inflammation Mediators - metabolism; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung - physiopathology; Mice, Inbred BALB C; Muscle, Smooth - drug effects; Muscle, Smooth - metabolism; Muscle, Smooth - pathology; Muscle, Smooth - physiopathology; Original; Ovalbumin; Protein Kinase Inhibitors - administration & dosage; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - physiopathology; Pyrimidines - administration & dosage; Transforming Growth Factor beta1 - metabolism; 내과학; Nilotinib; Airway remodeling; Fluticasone; Asthm
• ISSN: 1226-3303; 2005-6648; 2005-6648
• DOI: 10.3904/kjim.2015.002

Inhaled corticosteroids are the most effective treatment currently available for asthma, but their beneficial effect against airway remodeling is limited. The tyrosine kinase inhibitor nilotinib has inhibitory activity against c-kit and the platelet-derived growth factor receptor. We compared the effects of fluticasone and nilotinib on airway remodeling in a chronic asthma model. We also examined whether co-treatment with nilotinib and fluticasone had any synergistic effect in preventing airway remodeling. We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized female BALB/c-mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated with fluticasone and/or nilotinib intranasally during the OVA challenge. Mice chronically exposed to OVA developed eosinophilic airway inflammation and showed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Both fluticasone and nilotinib attenuated airway smooth muscle thickening. However, only nilotinib suppressed fibrotic changes, demonstrating inhibition of collagen deposition. Fluticasone reduced pro-inflammatory cells, such as eosinophils, and several cytokines, such as interleukin 4 (IL-4), IL-5, and IL-13, induced by repeated OVA challenges. On the other hand, nilotinib reduced transforming growth factor β1 levels in bronchoalveolar lavage fluid and inhibited fibroblast proliferation significantly. These results suggest that fluticasone and nilotinib suppressed airway remodeling in this chronic asthma model through anti-inflammatory and anti-fibrotic pathways, respectively.