Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, China.
Lung. 2014 Apr;192(2):267-75. doi: 10.1007/s00408-014-9561-1. Epub 2014 Feb 18.
Receptor for advanced glycation end products (RAGE), a multiple-ligands receptor, is implicated in chronic obstructive pulmonary disease (COPD). This study was designed to investigate the potential role of RAGE in nitric oxide (NO) generation, an endogenous marker of nitrosative stress in COPD.
Lung tissues from COPD patients were used to describe the relationship between RAGE expression and NO level. RAGE expression was assessed by immunohistochemistry, western blot, and ELISA. Human bronchial epithelial cells (16HBE) were cultured with cigarette smoke extract (CSE). Neutralizing antibody against RAGE was used to detect the role of RAGE in CSE-induced NO generation by 16HBE cells.
Compared with nonsmoker controls, overexpression of RAGE was significantly detected in COPD smokers (p < 0.01), but not healthy smokers and nonsmokers with COPD, which was dominantly expressed at bronchiolar epithelia. Correlation analysis showed that RAGE in COPD smokers was positively related to NO level, smoking status, and lung function decline. In cultured 16HBE cells treated with CSE, soluble RAGE was reduced; however, full-length RAGE was enhanced significantly as the same trend as NO generation. Moreover, increased NO level and NO synthase activity, decreased total glutathione (a major cellular antioxidant), enhanced nuclear translocation of p65 (a key molecule of nuclear factor (NF)-κB) and release of NF-κB-dependent proinflammatory cytokines were all reversed by pretreatment of anti-RAGE antibody.
These findings suggest that overexpression of RAGE contributes to CS-induced NO generation in COPD with involvement in NF-κB activation.
晚期糖基化终产物受体（RAGE）是一种多配体受体，与慢性阻塞性肺疾病（COPD）有关。本研究旨在探讨 RAGE 在 COPD 中一氧化氮（NO）生成（一种硝化应激的内源性标志物）中的潜在作用。
使用 COPD 患者的肺组织来描述 RAGE 表达与 NO 水平之间的关系。通过免疫组织化学、western blot 和 ELISA 来评估 RAGE 表达。用香烟烟雾提取物（CSE）培养人支气管上皮细胞（16HBE）。用 RAGE 的中和抗体来检测 16HBE 细胞中 CSE 诱导的 NO 生成中 RAGE 的作用。
与非吸烟者对照相比，COPD 吸烟者中 RAGE 的过度表达明显增加（p<0.01），但健康吸烟者和 COPD 非吸烟者中则没有增加，主要在细支气管上皮表达。相关性分析表明，COPD 吸烟者的 RAGE 与 NO 水平、吸烟状况和肺功能下降呈正相关。在经 CSE 处理的培养 16HBE 细胞中，可溶性 RAGE 减少；然而，全长 RAGE 显著增加，与 NO 生成呈相同趋势。此外，增加的 NO 水平和一氧化氮合酶活性、总谷胱甘肽（一种主要的细胞抗氧化剂）减少、p65（核因子（NF）-κB 的关键分子）核易位增强以及 NF-κB 依赖性促炎细胞因子的释放均被抗 RAGE 抗体预处理所逆转。
这些发现表明，RAGE 的过度表达导致 CS 诱导的 COPD 中 NO 的生成，涉及 NF-κB 的激活。
