Rationale: 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.

Objectives: To determine whether HMGB1 is augmented in COPD and is associated with IL-1β and RAGE.

Methods: 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-1β in human macrophages and in BAL fluid was examined.

Measurements and Main Results: 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-1β (r_s = 0.438; P = 0.0006) and negatively with FEV₁ (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-1β 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-α. RAGE was overexpressed in the airway epithelium and smooth muscle of patients with COPD and it colocalized with HMGB1.

Conclusions: Elevated HMGB1 expression in COPD airways may sustain inflammation and remodeling through its interaction with IL-1β and RAGE.