Kang Hye Seon, Rhee Chin Kook, Lee Hea Yon, Yoon Hyoung Kyu, Kwon Soon Seok, Lee Sook Young
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Yeouido St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Korean J Intern Med. 2016 Nov;31(6):1150-1158. doi: 10.3904/kjim.2015.002. Epub 2016 Oct 20.
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.
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.
背景/目的：吸入性糖皮质激素是目前治疗哮喘最有效的药物，但其对气道重塑的有益作用有限。酪氨酸激酶抑制剂尼洛替尼对c-kit和血小板衍生生长因子受体具有抑制活性。我们比较了氟替卡松和尼洛替尼对慢性哮喘模型气道重塑的影响。我们还研究了尼洛替尼与氟替卡松联合治疗在预防气道重塑方面是否具有协同作用。
我们建立了一种气道重塑的小鼠模型，包括平滑肌增厚，其中用卵清蛋白（OVA）致敏的雌性BALB/c小鼠每周两次经鼻反复给予OVA，持续3个月。在OVA激发期间，小鼠经鼻给予氟替卡松和/或尼洛替尼。
长期暴露于OVA的小鼠出现嗜酸性气道炎症，并表现出气道重塑的特征，包括支气管周围平滑肌层增厚。氟替卡松和尼洛替尼均减轻了气道平滑肌增厚。然而，只有尼洛替尼抑制了纤维化改变，证明其对胶原沉积有抑制作用。氟替卡松减少了由反复OVA激发诱导的促炎细胞，如嗜酸性粒细胞以及几种细胞因子，如白细胞介素4（IL-4）、IL-5和IL-13。另一方面，尼洛替尼降低了支气管肺泡灌洗液中转化生长因子β1的水平，并显著抑制了成纤维细胞增殖。
这些结果表明，氟替卡松和尼洛替尼在该慢性哮喘模型中分别通过抗炎和抗纤维化途径抑制气道重塑。
