Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Catholic University of Korea, Seoul, Korea.
Int Arch Allergy Immunol. 2011;155(3):243-51. doi: 10.1159/000321261. Epub 2011 Feb 2.
Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and remodeling. The tyrosine kinase inhibitor imatinib mesylate was developed to inhibit BCR-ABL kinase activity; however, it also has potent inhibitory activity against the c-Kit and platelet-derived growth factor receptors. The present study aimed to determine whether imatinib suppresses airway smooth muscle (ASM) remodeling and whether its effect is associated with growth factors such as transforming growth factor (TGF)-β1 and stem cell factor (SCF).
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 imatinib during the OVA challenge.
Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and AHR compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of imatinib significantly inhibited the development of AHR, eosinophilic inflammation and, importantly, ASM remodeling in mice chronically exposed to OVA. Imatinib treatment significantly reduced the levels of interleukin-4, -5 and -13. In addition, TGF-β1 and SCF were significantly reduced in the imatinib-treated animals.
These results suggest that imatinib administration can prevent not only airway inflammation, but also airway remodeling associated with chronic allergen challenge. Imatinib may provide a clinically attractive therapy for chronic severe asthma.
哮喘的特征是气道高反应性（AHR）、炎症和重塑。甲磺酸伊马替尼是为抑制 BCR-ABL 激酶活性而开发的酪氨酸激酶抑制剂；然而，它对 c-Kit 和血小板衍生生长因子受体也具有很强的抑制活性。本研究旨在确定伊马替尼是否抑制气道平滑肌（ASM）重塑，以及其作用是否与转化生长因子（TGF）-β1 和干细胞因子（SCF）等生长因子有关。
我们建立了一种气道重塑的小鼠模型，其中包括平滑肌增厚，在该模型中，卵清蛋白（OVA）致敏的小鼠每周两次接受鼻内 OVA 给药，持续 3 个月。在 OVA 挑战期间，用伊马替尼对小鼠进行治疗。
与对照组小鼠相比，慢性暴露于 OVA 的小鼠持续发生嗜酸性气道炎症和 AHR。此外，慢性暴露于 OVA 的小鼠出现气道重塑的特征，包括支气管周围平滑肌层增厚。伊马替尼给药显著抑制慢性暴露于 OVA 的小鼠 AHR、嗜酸性炎症的发展，重要的是，还抑制 ASM 重塑。伊马替尼治疗显著降低了白细胞介素-4、-5 和 -13 的水平。此外，伊马替尼处理的动物中 TGF-β1 和 SCF 水平显著降低。
这些结果表明，伊马替尼给药不仅可以预防气道炎症，还可以预防与慢性变应原挑战相关的气道重塑。伊马替尼可能为慢性严重哮喘提供一种有吸引力的临床治疗方法。
