Department of Medicine, University of California San Diego, San Diego, CA, United States.
Int Immunopharmacol. 2011 Aug;11(8):1038-44. doi: 10.1016/j.intimp.2011.02.024. Epub 2011 Mar 5.
The role of tumor necrosis factor-α (TNF-α) in contributing to allergen induced airway remodeling in asthma is unknown. In this study we have utilized a mouse model of chronic OVA allergen induced airway remodeling to determine whether TNF p55/p75 receptor deficient mice (abbreviated TNF-R KO) had reduced levels of airway remodeling. Chronic OVA challenged WT mice had significantly increased levels of lung eosinophilic inflammation as well as features of airway remodeling including increased peribronchial fibrosis, thickness of the peribronchial smooth muscle layer, mucus expression, and deposition of extracellular matrix proteins. In contrast, TNF-R KO mice had significantly reduced levels of major basic protein positive peribronchial eosinophils and significantly reduced peribronchial fibrosis assessed by quantitating the area of peribronchial trichrome staining and total lung collagen. In addition, TNF-R KO mice had significantly reduced thickness of the peribronchial smooth muscle layer, area of peribronchial α-smooth muscle actin immunostaining, and levels of the extracellular matrix protein fibronectin. There was a non-significant trend for reduced mucus expression in TNF-R KO mice. Levels of peribronchial cells immunostaining positive for TGF-β1 were significantly reduced in TNF-R KO mice suggesting that reduced levels of TGF-β1 expression in TNF-R KO mice may contribute to reduced airway remodeling. Overall, this study suggests an important role for TNF-α in contributing to many features of allergen induced airway remodeling including changes in levels of peribronchial smooth muscle, subepithelial fibrosis, and deposition of extracellular matrix.
肿瘤坏死因子-α（TNF-α）在哮喘中导致过敏原诱导的气道重塑中的作用尚不清楚。在这项研究中，我们利用慢性 OVA 过敏原诱导的气道重塑小鼠模型来确定 TNF p55/p75 受体缺陷（简称 TNF-R KO）小鼠是否具有较低水平的气道重塑。慢性 OVA 挑战的 WT 小鼠具有显著增加的肺嗜酸性粒细胞炎症以及气道重塑的特征，包括增加的支气管周围纤维化、支气管周围平滑肌层的厚度、粘液表达和细胞外基质蛋白的沉积。相比之下，TNF-R KO 小鼠具有显著减少的主要碱性蛋白阳性支气管周围嗜酸性粒细胞，并且通过定量支气管周围三染色和总肺胶原评估支气管周围纤维化具有显著减少的支气管周围纤维化。此外，TNF-R KO 小鼠具有显著减少的支气管周围平滑肌层的厚度、支气管周围α-平滑肌肌动蛋白免疫染色的面积和细胞外基质蛋白纤连蛋白的水平。TNF-R KO 小鼠的粘液表达减少具有非显著趋势。TNF-R KO 小鼠的支气管周围细胞免疫染色阳性 TGF-β1 的水平显著降低，这表明 TNF-R KO 小鼠中 TGF-β1 表达水平降低可能导致气道重塑减少。总体而言，这项研究表明 TNF-α 在导致过敏原诱导的气道重塑的许多特征中具有重要作用，包括支气管周围平滑肌、上皮下纤维化和细胞外基质沉积水平的变化。
