Centre de recherche, Centre hospitalier de l’Université de Montréal, Hôtel-Dieu, Montréal, Québec, Canada.
Am J Physiol Lung Cell Mol Physiol. 2011 Dec;301(6):L945-55. doi: 10.1152/ajplung.00149.2011. Epub 2011 Sep 9.
Chronic infection and inflammation have been associated with progressive airway epithelial damage in patients with cystic fibrosis (CF). However, the effect of inflammatory products on the repair capacity of respiratory epithelia is unclear. Our objective was to study the regulation of repair mechanisms by tumor necrosis factor-α (TNF-α), a major component of inflammation in CF, in a model of mechanical wounding, in two bronchial cell lines, non-CF NuLi and CF CuFi. We observed that TNF-α enhanced the NuLi and CuFi repair rates. Chronic exposure (24-48 h) to TNF-α augmented this stimulation as well as the migration rate during repair. The cellular mechanisms involved in this stimulation were then evaluated. First, we discerned that TNF-α induced metalloproteinase-9 release, epidermal growth factor (EGF) shedding, and subsequent EGF receptor transactivation. Second, TNF-α-induced stimulation of the NuLi and CuFi wound-closure rates was prevented by GM6001 (metalloproteinase inhibitor), EGF antibody (to titrate secreted EGF), and EGF receptor tyrosine kinase inhibitors. Furthermore, we recently reported a relationship between the EGF response and K(+) channel function, both controlling bronchial repair. We now show that TNF-α enhances KvLQT1 and K(ATP) currents, while their inhibition abolishes TNF-α-induced repair stimulation. These results indicate that the effect of TNF-α is mediated, at least in part, through EGF receptor transactivation and K(+) channel stimulation. In contrast, cell proliferation during repair was slowed by TNF-α, suggesting that TNF-α could exert contrasting actions on repair mechanisms of CF airway epithelia. Finally, the stimulatory effect of TNF-α on airway wound repair was confirmed on primary airway epithelial cells, from non-CF and CF patients.
慢性感染和炎症与囊性纤维化（CF）患者气道上皮的进行性损伤有关。然而，炎症产物对呼吸上皮修复能力的影响尚不清楚。我们的目的是在机械性创伤模型中研究肿瘤坏死因子-α（TNF-α）（CF 炎症的主要成分）对两种支气管细胞系（非 CF NuLi 和 CF CuFi）修复机制的调节作用。我们观察到 TNF-α增强了 NuLi 和 CuFi 的修复率。慢性暴露（24-48 小时）于 TNF-α增强了这种刺激以及修复过程中的迁移率。然后评估了参与这种刺激的细胞机制。首先，我们发现 TNF-α诱导了金属蛋白酶-9 的释放、表皮生长因子（EGF）的脱落以及随后的表皮生长因子受体转位激活。其次，GM6001（金属蛋白酶抑制剂）、EGF 抗体（滴定分泌的 EGF）和表皮生长因子受体酪氨酸激酶抑制剂可阻止 TNF-α诱导的 NuLi 和 CuFi 伤口闭合率的刺激。此外，我们最近报道了 EGF 反应和 K(+)通道功能之间的关系，两者都控制着支气管修复。我们现在表明，TNF-α增强了 KvLQT1 和 K(ATP)电流，而其抑制作用则消除了 TNF-α诱导的修复刺激。这些结果表明，TNF-α的作用至少部分是通过表皮生长因子受体转位激活和 K(+)通道刺激来介导的。相比之下，TNF-α在修复过程中减缓了细胞增殖，表明 TNF-α可能对 CF 气道上皮的修复机制产生相反的作用。最后，在非 CF 和 CF 患者的原代气道上皮细胞上证实了 TNF-α对气道伤口修复的刺激作用。
