Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells
Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells
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DOI：
10.1136/thoraxjnl-2013-203520
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发表时间：
2014-01-01
期刊：
影响因子：
10
通讯作者：
van den Berge, Maarten
中科院分区：
文献类型：
--
作者：
Heijink, Irene;van Oosterhout, Antoon;van den Berge, Maarten
背景我们假设，哮喘和慢性阻塞性肺病（COPD）患者气道中存在的氧化应激增加，诱导上皮损伤并降低上皮对皮质类固醇对促炎细胞因子产生和屏障功能的抑制作用的反应性。在人支气管上皮16 HBE细胞和通过来自哮喘患者、COPD患者以及吸烟和不吸烟对照个体的刷拭衍生的原代支气管上皮细胞（PBEC）中。我们研究了布地奈德对屏障功能（电阻）和TNF-α诱导的促炎细胞因子（IL-8/CXCL 8、粒细胞巨噬细胞集落刺激因子（GM-CSF））产生的影响。布地奈德显著抵消了这种作用，可能是通过保护表皮生长因子受体依赖性细胞-细胞接触破坏。此外，布地奈德抑制促炎细胞因子的产生。H2 O2预处理降低了布地奈德对16 HBE细胞和PBEC细胞因子产生的影响。重要的是，从哮喘和COPD患者的PBECs不太敏感，布地奈德的细胞因子的生产和屏障功能比PBECs从control subjects.Conclusions，我们的数据表明，布地奈德抑制上皮促炎反应和屏障功能障碍，氧化应激减少这些影响在哮喘和COPD患者的气道上皮。因此，在哮喘和COPD中皮质类固醇反应性的恢复可能起到改善气道上皮屏障的作用。
Background We hypothesised that increased oxidative stress, as present in the airways of asthma and chronic obstructive pulmonary disease (COPD) patients, induces epithelial damage and reduces epithelial responsiveness to suppressive effects of corticosteroids on proinflammatory cytokine production and barrier function.Methods We induced oxidative stress by H2O2 and/or cigarette smoke extract (CSE) in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBEC) derived by brushings from asthma patients, COPD patients, and smoking and non-smoking control individuals. We investigated effects of budesonide on barrier function (electrical resistance) and TNF-alpha-induced proinflammatory cytokine production (IL-8/CXCL8, granulocyte macrophage-colony stimulating factor (GM-CSF)).Results We observed that H2O2 and CSE reduce epithelial resistance. Budesonide significantly counteracted this effect, likely by protection against epidermal growth factor receptor-dependent cell-cell contact disruption. Furthermore, budesonide suppressed proinflammatory cytokine production. H2O2 pretreatment reduced this effect of budesonide on cytokine production in both 16HBE cells and PBECs. Importantly, PBECs from asthma and COPD patients were less sensitive to budesonide with respect to cytokine production and barrier function than PBECs from control subjects.Conclusions Together, our data indicate that budesonide suppresses epithelial proinflammatory responses and barrier dysfunction and that oxidative stress reduces these effects in airway epithelium from asthma and COPD patients. Therefore, restoration of corticosteroid responsiveness in asthma and COPD may act to improve the airway epithelial barrier.