A Study On Airway Remodeling Of Chronic Asthmatic Mouse Model Intervened By Muti-receptor Tyrosine Kinase Inhibitor

Objective:Airway inflammation and remodeling in chronic asthma are characterized by airway eosinophilia,lymphocytosis,mastocytosis,hyperplasia of goblet cells and smooth muscle,subepithelial fibrosis and submucosal vascular proliferation.The study aims to investigate the influence on airway remodeling which results from the blocking of corresponding pathways caused by receptor tyrosine kinase inhibitor- sunitinib.Meanwhile a comparison parison is made to figure out the distinctions between sunitinib and glucocorticosteroid intervention.Furthermore,the application prospect of receptor tyrosine kinase inhibitor in the cure of asthma is discussed.Methods:60 BALB/c mice are evenly divided into five groups at random. They are normal group(Group A),the group of asthma airway remodeling (Group B),the group of sunitinib intervention(Group C),the group of glucocorticosteroid intervention(Group D)and the combined group of sunitinib and glucocorticosteroid intervention(Group E).The asthmatic model is established by the sensitization and challenged of ovalbumin at the concentration of 10%and 1%respectively.The respective state of lung function in each group is measured by the lung function instrument.The airway inflammation, inflammatory cell infiltration,collagen deposition and hyperplasia of goblet cells are observed by the means of hematoxylin and eosin staining,masson trichrome staining and periodic acid-schiff staining.The expression and location ofα-Smooth muscle actin in lung are observed by the means of immunohistochemistry. The change of airway wall and smooth muscle are observed by computer-assisted image analysis software.The immunoglobulin E(IgE) in the mice serum and the expression of interleukin 13(IL13)in bronchoalveolar lavage fluid are observed by the means of enzyme linked immunosorbent assay(Elisa).The phosphorylation of c-kit receptor in the mice lung is observed by the means of Immunoprecipitation/Western blot.Results:The detection of expiratory resistance reveals that the expiratory resistance of Group C,D and E is(22.57±2.42)cmH₂0·ml^-1·s^-1,(24.45±1.54) cmH₂O·ml^-1·s^-1and(19.94±0.97)cmH₂O·ml^-1·s^-1respectively when the concentration of Acetylcholine Chloride is 45μg/kg,which indicates a statistical significance(P＜0.05)in comparison with that of Group B(33.77±1.85) cmH₂O·ml^-1·s.(-1).Ratio between the area of airway wall and the circumference of basement membrane of Group C,D and E are(16.68±0.41),(24.56±1.20), (15.08±0.16)respectively which indicates a statistical significance(P＜0.05)in comparison with that of Group B(51.98±2.54).Ratio between the area of collagen and the circumference of basement membrane of Group C,D and E are(7.42±0.17),(12.62±1.18),(5.73±0.44)respectively which indicates a statistical significance(P＜0.05)in comparison with that of Group B(45.14±1.26).Ratio between the area of ABPAS(+)and the circumference of basement membrane of Group C,D and E are(0.54±0.50),(0.93±0.06), (0.30±0.11)respectively which indicates a statistical significance(P＜0.05)in comparison with that of Group B(5.12±0.46).Ratio between the area of bronchial smooth muscle actin and the circumference of basement membrane of Group C,D and E are(9.06±0.36),(5.26±0.50),(4.28±0.14)respectively which indicates a statistical significance(P＜0.05)in comparison with that of Group B(18.30±0.89).By the means of Elisa,it reveals that the amount of sera IgE in Group C,D and E is(0.86±0.08)ng/ml,(0.94±0.14)ng/ml, (0.63±0.16)ng/ml respectively which indicates a statistical significance(P＜0.05)in comparison with that of Group B(2.21±0.30).Meanwhile the amount of IL13 of bronchoalveolar lavage fluid in Group C,D and E is(96.39±1.70) pg/ml,(97.66±5.49)pg/ml and(92.26±4.76)pg/ml respectively,which indicates a significant difference in comparison with that of Group B(P＜0.05). By the means of IP/Western-blot,it reveals that the extent of phosphorylation of c-kit receptor in Group C,D and E is(0.063±0.009),(0.108±0.012)and (0.048±0.009)respectively which indicates a significant difference(P＜0.05)in comparison with that of Group B(0.434±0.040).Conclusions:Receptor tyrosine kinase inhibitor-sunitinib could block the phosphorylation of c-kit receptor,alleviate the reaction of airway inflammation and inhibit airway remodeling.The effect of sunitinib is equivalent to glucocorticosteroid.The combination of medicines may produce a better treatment effect.