Laboratory of Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, , Groningen, The Netherlands.
Thorax. 2014 Jan;69(1):5-13. doi: 10.1136/thoraxjnl-2013-203520. Epub 2013 Aug 26.
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.
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-α-induced proinflammatory cytokine production (IL-8/CXCL8, granulocyte macrophage-colony stimulating factor (GM-CSF)).
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.
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.
我们假设，哮喘和慢性阻塞性肺疾病（COPD）患者气道中存在的氧化应激会导致上皮细胞损伤，并降低上皮细胞对皮质类固醇抑制促炎细胞因子产生和屏障功能的抑制作用的反应性。
我们通过 H2O2 和/或香烟烟雾提取物（CSE）在人支气管上皮细胞 16HBE 和来源于哮喘患者、COPD 患者以及吸烟和非吸烟对照个体的支气管上皮细胞刷取物中诱导氧化应激。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产生（IL-8/CXCL8、粒细胞巨噬细胞集落刺激因子（GM-CSF））的影响。
我们观察到 H2O2 和 CSE 降低了上皮细胞的电阻。布地奈德显著拮抗了这种作用，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，布地奈德抑制了促炎细胞因子的产生。H2O2 预处理降低了布地奈德对 16HBE 细胞和 PBEC 中细胞因子产生的这种抑制作用。重要的是，与对照个体的 PBEC 相比，哮喘和 COPD 患者的 PBEC 对布地奈德在细胞因子产生和屏障功能方面的敏感性降低。
综上所述，我们的数据表明，布地奈德抑制上皮细胞的促炎反应和屏障功能障碍，而氧化应激会降低哮喘和 COPD 气道上皮细胞中这些作用。因此，恢复哮喘和 COPD 中皮质类固醇的反应性可能会改善气道上皮屏障。
