Institut National de la Santé et de la Recherche Médicale (INSERM) U700, Physiopathologie et Epidémiologie de l'Insuffisance Respiratoire, Paris, France.
Am J Respir Crit Care Med. 2010 May 1;181(9):917-27. doi: 10.1164/rccm.200903-0340OC. Epub 2010 Feb 4.
Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation and remodeling. High-mobility group box 1 (HMGB1), a nuclear protein that is released during inflammation and repair, interacts with proinflammatory cytokines and with the receptor for advanced glycation end products (RAGE), which is highly expressed in the lung.
To determine whether HMGB1 is augmented in COPD and is associated with IL-1beta and RAGE.
HMGB1 was assessed in the bronchoalveolar lavage (BAL) of 20 never-smokers, 20 smokers, and 30 smokers with COPD and it was correlated with inflammatory and clinical parameters. In parallel, HMGB1 and RAGE immunolocalization was determined in bronchial and lung tissues. Last, binding of HMGB1 to IL-1beta in human macrophages and in BAL fluid was examined.
BAL levels of HMGB1 were higher in smokers with COPD than in smokers and never-smokers (P < 0.0001 for both comparisons), and similar differences were observed in epithelial cells and alveolar macrophages. BAL HMGB1 correlated positively with IL-1beta (r(s) = 0.438; P = 0.0006) and negatively with FEV(1) (r(s) = -0.570; P < 0.0001) and transfer factor of the lung for carbon monoxide (r(s) = -0.382; P = 0.0026). HMGB1-IL-1beta complexes were found in BAL supernatant and alveolar macrophages from smokers and patients with COPD, as well as in the human macrophage cell line, THP-1, where they enhanced the synthesis of tumor-necrosis factor-alpha. RAGE was overexpressed in the airway epithelium and smooth muscle of patients with COPD and it colocalized with HMGB1.
Elevated HMGB1 expression in COPD airways may sustain inflammation and remodeling through its interaction with IL-1beta and RAGE.
慢性阻塞性肺疾病（COPD）的特征是气道炎症和重塑。高迁移率族蛋白 1（HMGB1）是一种在炎症和修复过程中释放的核蛋白，它与促炎细胞因子相互作用，并与在肺部高表达的晚期糖基化终产物受体（RAGE）相互作用。
确定 HMGB1 是否在 COPD 中增加，并与 IL-1beta 和 RAGE 相关。
在 20 名不吸烟者、20 名吸烟者和 30 名 COPD 吸烟者的支气管肺泡灌洗液（BAL）中评估 HMGB1，并将其与炎症和临床参数相关联。同时，在支气管和肺组织中确定 HMGB1 和 RAGE 的免疫定位。最后，检查 HMGB1 与人巨噬细胞和 BAL 液中 IL-1beta 的结合。
COPD 吸烟者的 BAL 中 HMGB1 水平高于吸烟者和不吸烟者（两者比较均 P < 0.0001），上皮细胞和肺泡巨噬细胞中也观察到类似的差异。BAL HMGB1 与 IL-1beta 呈正相关（r(s) = 0.438；P = 0.0006），与 FEV(1)（r(s) = -0.570；P < 0.0001）和肺一氧化碳转移因子（r(s) = -0.382；P = 0.0026）呈负相关。在吸烟者和 COPD 患者的 BAL 上清液和肺泡巨噬细胞以及人巨噬细胞系 THP-1 中均发现 HMGB1-IL-1beta 复合物，它们增强肿瘤坏死因子-α的合成。在 COPD 患者的气道上皮和平滑肌中 RAGE 过度表达，并与 HMGB1 共定位。
COPD 气道中 HMGB1 的表达升高可能通过与 IL-1beta 和 RAGE 的相互作用来维持炎症和重塑。
