Korean J Intern Med.  2016 Nov;31(6):1150-1158. 10.3904/kjim.2015.002.

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

• Kang HS
• Rhee CK
• Lee HY
• Yoon HK
• Kwon SS
• Lee SY

• KMID: 2382865
• DOI: http://doi.org/10.3904/kjim.2015.002

Abstract

BACKGROUND/AIMS
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
These results suggest that fluticasone and nilotinib suppressed airway remodeling in this chronic asthma model through anti-inflammatory and anti-fibrotic pathways, respectively.

Keyword

Asthm; Nilotinib; Fluticasone; Airway remodeling

MeSH Terms

Adrenal Cortex Hormones
Airway Remodeling
Animals
Asthma*
Bronchoalveolar Lavage Fluid
Collagen
Cytokines
Eosinophils
Female
Fibroblasts
Fluticasone*
Hand
Humans
Inflammation
Interleukin-13
Interleukin-4
Interleukin-5
Mice
Muscle, Smooth
Ovalbumin
Ovum
Protein-Tyrosine Kinases
Receptors, Platelet-Derived Growth Factor
Transforming Growth Factors
Adrenal Cortex Hormones
Collagen
Cytokines
Fluticasone
Interleukin-13
Interleukin-4
Interleukin-5
Ovalbumin
Protein-Tyrosine Kinases
Receptors, Platelet-Derived Growth Factor
Transforming Growth Factors