Different anti-remodeling effect of nilotinib and fluticasone in a chronic asthma model
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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 f luticasone 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.
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 f luticasone 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.
참고문헌 (37)
- Sumi Y, "Airway remodeling in asthma", Allergol Int, 56, pp.341~348 (2007)
- Prakash YS, "Airway smooth muscle in airway reactivity and remodeling: what have we learned?", Am J Physiol Lung Cell Mol Physiol, 305, pp.L912~L933 (2013)
- Manuyakorn W, "Airway remodelling in asthma and novel therapy", Asian Pac J Allergy Immunol, 31, pp.3~10 (2013)
- Chetta A, "Vascular component of airway remodeling in asthma is reduced by high dose of fluticasone", Am J Respir Crit Care Med, 167, pp.751~757 (2003)
- Lee SY, "Inhaled corticosteroid prevents the thickening of airway smooth muscle in murine model of chronic asthma", Pulm Pharmacol Ther, 21, pp.14~19 (2008)
- Yick CY, "Glucocorticoid-induced changes in gene expression of airway smooth muscle in patients with asthma", Am J Respir Crit Care Med, 187, pp.1076~1084 (2013)
- Bergeron C, "Evidence of remodeling in peripheral airways of patients with mild to moderate asthma: effect of hydrofluoroalkane-flunisolide", J Allergy Clin Immunol, 116, pp.983~989 (2005)
- Chakir J, "Airway remodeling-associated mediators in moderate to severe asthma:effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression", J Allergy Clin Immunol, 111, pp.1293~1298 (2003)
- Royce SG, "Combination therapy with relaxin and methylprednisolone augments the effects of either treatment alone in inhibiting subepithelial fibrosis in an experimental model of allergic airways disease", Clin Sci, 124, pp.41~51 (2013)
- Rhee CK, "Effect of imatinib on airway smooth muscle thickening in a murine model of chronic asthma", Int Arch Allergy Immunol, 155, pp.243~251 (2011)
- Rhee CK, "Effect of nilotinib on airway remodeling in a murine model of chronic asthma", Exp Lung Res, 40, pp.199~210 (2014)
- Ostendorf BN, "Nilotinib", Recent Results Cancer Res, 201, pp.67~80 (2014)
- Distler JH, "Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosis", Rheumatology, 47(Suppl 5), pp.v10~v11 (2008)
- Gordon JK, "Targeting tyrosine kinases: a novel therapeutic strategy for systemic sclerosis", Curr Opin Rheumatol, 22, pp.690~695 (2010)
- Rhee CK, "Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice", Respiration, 82, pp.273~287 (2011)
- Shiha GE, "Tracking anti-fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: an insight", Clin Exp Pharmacol Physiol, 41, pp.788~797 (2014)
- Al-Alawi M, "Transforming growth factor β and severe asthma: a perfect storm", Respir Med, 108, pp.1409~1423 (2014)
- Descalzi D, "Anti-proliferative and anti-remodelling effect of beclomethasone dipropionate, formoterol and salbutamol alone or in combination in primary human bronchial fibroblasts", Allergy, 63, pp.432~437 (2008)
- Tschumperlin DJ, "Mechanical stimuli to airway remodeling", Am J Respir Crit Care Med, 164(10Pt 2), pp.S90~S94 (2001)
- Ressler B, "Molecular responses of rat tracheal epithelial cells to transmembrane pressure", Am J Physiol Lung Cell Mol Physiol, 278, pp.L1264~L1272 (2000)
- Grainge CL, "Effect of bronchoconstriction on airway remodeling in asthma", N Engl J Med, 364, pp.2006~2015 (2011)
- Reber L, "Stem cell factor and its receptor c-Kit as targets for inflammatory diseases", Eur J Pharmacol, 533, pp.327~340 (2006)
- El-Agamy DS, "Targeting c-kit in the therapy of mast cell disorders: current update", Eur J Pharmacol, 690, pp.1~3 (2012)
- Carlin SM, "Urokinase potentiates PDGF-induced chemotaxis of human airway smooth muscle cells", Am J Physiol Lung Cell Mol Physiol, 284, pp.L1020~L1026 (2003)
- Berlin AA, "Inhibition of SCF attenuates peribronchial remodeling in chronic cockroach allergen-induced asthma", Lab Invest, 86, pp.557~565 (2006)
- Distler JH, "Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis:towards molecular targeted therapies", Ann Rheum Dis, 69(Suppl 1), pp.i48~i51 (2010)
- Bottoms SE, "Tgf-Beta isoform specific regulation of airway inflammation and remodelling in a murine model of asthma", PLoS One, 5, pp.e9674~ (2010)
- Redington AE, "Transforming growth factor-beta 1 in asthma. Measurement in bronchoalveolar lavage fluid", Am J Respir Crit Care Med, 156(2 Pt 1), pp.642~647 (1997)
- Michalik M, "Asthmatic bronchial fibroblasts demonstrate enhanced potential to differentiate into myofibroblasts in culture", Med Sci Monit, 15, pp.BR194~BR201 (2009)
- Kumawat K, "Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells", FASEB J, 27, pp.1631~1643 (2013)
- Oenema TA, "Cross-talk between transforming growth factor-β1 and muscarinic M2receptors augments airway smooth muscle proliferation", Am J Respir Cell Mol Biol, 49, pp.18~27 (2013)
- Makinde T, "The regulatory role of TGF-beta in airway remodeling in asthma", Immunol Cell Biol, 85, pp.348~356 (2007)
- Howell JE, "TGF-beta: its role in asthma and therapeutic potential", Curr Drug Targets, 7, pp.547~565 (2006)
- Liu Y, "Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib", J Hepatol, 55, pp.612~625 (2011)
- Vanacker NJ, "Fluticasone inhibits but does not reverse allergen-induced structural airway changes", Am J Respir Crit Care Med, 163(3 Pt 1), pp.674~679 (2001)
- Olivieri D, "Effect of shortterm treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo-controlled study", Am J Respir Crit Care Med, 155, pp.1864~1871 (1997)
- Hirota N, "Mechanisms of airway remodeling", Chest, 144, pp.1026~1032 (2013)