Effect of nilotinib on airway remodeling in a murine model of chronic asthma.
ABSTRACT Objective: The tyrosine kinase inhibitor nilotinib has potent inhibitory activity against the stem cell growth factor receptor c-Kit and platelet-derived growth factor receptor (PDGFR). The present study aimed to determine whether nilotinib suppresses airway remodeling and whether its effect is associated with the c-Kit and PDGFR pathways. We also aimed to compare the effect of nilotinib and imatinib on remodeling.


METHODS
We developed a mouse model of airway remodeling, which includes smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated with nilotinib or imatinib during the OVA challenge.


RESULTS
Compared with control mice, the mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, airway hyperresponsiveness (AHR), and exhibited features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of nilotinib significantly inhibited eosinophilic inflammation, AHR, and remodeling in mice chronically exposed to OVA. Nilotinib showed a trend of more potent effect than imatinib on attenuating remodeling in hydroxyproline assay and smooth muscle staining. Nilotinib treatment significantly reduced the expression of phosphorylated (p)-c-Kit, p-PDGFRβ, and p-extracellular signal-regulated kinase 1/2. The expression levels of the genes encoding c-Kit and PDGFRβ were also reduced by nilotinib treatment. Treatment with nilotinib did not affect significantly the level of OVA-specific IgE and IgG1 in serum. In vitro, nilotinib significantly inhibited cell proliferation of fibroblast.


CONCLUSIONS
These results suggest that nilotinib administration can prevent airway inflammation, AHR, and airway remodeling associated with chronic allergen challenge.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Chin Kook
CK
Rhee
Ji Young
JY
Kang
Chan Kwon
CK
Park
Sook Young
SY
Lee
Soon Suk
SS
Kwon
Young Kyoon
YK
Kim
Hyoung Kyu
HK
Yoon
D000199:Actins / Q000032:analysis; D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D006909:Hydroxyproline / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis / Q000235:genetics
D000199:Actins; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D011743:Pyrimidines; C544013:alpha-smooth muscle actin, mouse; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; C498826:nilotinib; D006909:Hydroxyproline