Allergen-induced peribronchial fibrosis and mucus production mediated by IκB kinase β-dependent genes in airway epithelium
Allergen-induced peribronchial fibrosis and mucus production mediated by IκB kinase β-dependent genes in airway epithelium
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DOI：
10.1073/pnas.0509235102
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发表时间：
2005-12-06
影响因子：
11.1
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Broide, DH;Lawrence, T;Karin, M
在炎症或损伤的反应中，气道上皮细胞表达可诱导基因，这些基因可能有助于过敏原诱导的气道重塑。为了确定上皮细胞NF-κ B活化对重塑反应的贡献，我们产生了CC 10-Cre（tg）/ikk β（Delta/Delta）小鼠，其中通过来自Clara细胞（CC 10）启动子的条件性Cre重组酶表达在气道上皮中选择性地消融通过I κ B激酶β（IKK β）的NF-κ B信号传导。通过支气管周围三色染色和肺总胶原含量评估，对气道上皮lKK β缺陷小鼠进行反复卵清蛋白激发，仅在气道上皮细胞中阻止ReIA NF-κ B亚基的核转位，导致CC 10-Cre（tg）/Ikk β（Delta/Delta）小鼠的支气管周围纤维化显著低于同窝对照小鼠。在卵白蛋白激发的小鼠中，气道粘液、气道嗜酸性粒细胞和支气管周围CD 4（+）细胞的水平在气道上皮Ikk β消融后也显著降低。炎症反应的减弱与NF-κ B调节的趋化因子表达减少有关，包括嗜酸性粒细胞趋化因子-1和胸腺和活化调节的趋化因子，它们分别吸引嗜酸性粒细胞和Th 2细胞进入气道。表达TGF-β 1的支气管周围细胞的数量，以及支气管肺泡灌洗液中TGF-β 1的量，在气道上皮lKK β缺陷的小鼠中也显著减少。总之，这些研究表明，在过敏原诱导的气道重塑，包括支气管周围纤维化和粘液产生的气道上皮细胞中的NF-κ B调节基因的重要作用。
In response to inflammation or injury, airway epithelial cells express inducible genes that may contribute to allergen-induced airway remodeling. To determine the contribution of epithelial cell NF-kappa B activation to the remodeling response, we generated CC10-Cre(tg)/ikk beta(Delta/Delta) mice in which NF-KB signaling through I kappa B kinase beta (IKK beta) is selectively ablated in the airway epithelium by conditional Cre-recombinase expression from the Clara cell (CC10) promoter. Repetitive ovalbumin challenge of mice deficient in airway epithelial lKK beta prevented nuclear translocation of the ReIA NF-KB subunit only in airway epithelial cells, resulting in significantly lower peribronchial fibrosis in CC10-Cre(tg)/Ikk beta(Delta/Delta) mice compared with littermate controls as assessed by peribronchial trichrome staining and total lung collagen content. Levels of airway mucus, airway eosinophils, and peribronchial CD4(+) cells in ovalbumin-challenged mice were also reduced significantly upon airway epithelial Ikk beta ablation. The diminished inflammatory response was associated with reduced expression of NF-kappa B-regulated chemokines, including eotaxin-1 and thymus- and activation-regulated chemokine, which attract eosinophils and Th2 cells, respectively, into the airway. The number of peribronchial cells expressing TGF-beta 1, as well as TGF-beta 1 amounts in bronchoalveolar lavage, were also significantly reduced in mice deficient in airway epithelium lKK beta. Overall, these studies show an important role for NF-KB regulated genes in airway epithelium in allergen-induced airway remodeling, including peribronchial fibrosis and mucus production.