Manipulation of allergen-induced airway remodeling by treatment with anti-TGF-β antibody:: Effect on the Smad signaling pathway
Manipulation of allergen-induced airway remodeling by treatment with anti-TGF-β antibody:: Effect on the Smad signaling pathway
复制标题
DOI：
10.4049/jimmunol.174.9.5774
复制
发表时间：
2005-05-01
影响因子：
4.4
通讯作者：
Lloyd, CM
中科院分区：
文献类型：
--
作者：
McMillan, SJ;Xanthou, G;Lloyd, CM
气道炎症和气道重塑是慢性哮喘的重要病理生理特征。以前，我们已经开发了一种小鼠模型的长期过敏原的挑战，表现出慢性哮喘的许多特点，如杯状细胞增生和上皮下胶原沉积，与肺表达的促纤维化介质，TGF-β的增加。本研究的目的是确定阻断TGF-β对气道炎症和重塑的发展的影响，使用我们的小鼠模型的长期过敏原的挑战。重要的是，治疗性地施用抗TGF-β Ab，在建立的嗜酸性气道炎症发作后开始给药。用抗TGF-β Ab治疗小鼠显著减少了支气管周围细胞外基质沉积、气道平滑肌细胞增殖和肺中粘液产生，而不影响已建立的气道炎症和Th 2细胞因子产生。因此，我们的数据表明，在长期过敏原激发过程中，气道炎症和重塑可能是不相关的。此外，抗TGF-β Ab治疗显示原位调节活性TGF-β信号传导，肺切片中磷酸化Smad 2表达减少，同时Smad 7上调。因此，这是第一份报告表明，即使在治疗模式下给予抗TGF-β抗体治疗，也能防止过敏原激发后气道重塑的进展。此外，这种效应背后的分子机制可能涉及调节活性TGF-β信号传导。
Airway inflammation and remodeling are important pathophysiologic features of chronic asthma. Previously, we have developed a mouse model of prolonged allergen challenge which exhibits many characteristics of chronic asthma such as goblet cell hyperplasia and subepithelial collagen deposition, in association with an increase in lung expression of the profibrotic mediator, TGF-beta. The aim of this study was to determine the effects of blockade of TGF-beta on the development of airway inflammation and remodeling using our murine model of prolonged allergen challenge. Importantly anti-TGF-beta Ab was administered therapeutically, with dosing starting after the onset of established eosinophilic airway inflammation. Therapeutic treatment of mice with anti-TGF-beta Ab significantly reduced peribronchiolar extracellular matrix deposition, airway smooth muscle cell proliferation, and mucus production in the lung without affecting established airway inflammation and Th2 cytokine production. Thus, our data suggest that it might be possible to uncouple airway inflammation and remodeling during prolonged allergen challenge. In addition, anti-TGF-beta Ab treatment was shown to regulate active TGF-beta signaling in situ with a reduction in the expression of phospho-Smad 2 and the concomitant up-regulation of Smad 7 in lung sections. Therefore, this is the first report to suggest that anti-TGF-beta Ab treatment prevents the progression of airway remodeling following allergen challenge even when given in a therapeutic mode. Moreover, the molecular mechanism behind this effect may involve regulation of active TGF-beta signaling.