Expression of high-mobility group box 1 and of receptor for advanced glycation end products in chronic obstructive pulmonary disease.
BACKGROUND
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.


OBJECTIVE
To determine whether HMGB1 is augmented in COPD and is associated with IL-1beta 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-1beta in human macrophages and in BAL fluid was examined.


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-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.


CONCLUSIONS
Elevated HMGB1 expression in COPD airways may sustain inflammation and remodeling through its interaction with IL-1beta and RAGE.
Institut National de la Santé et de la Recherche Médicale (INSERM) U700, Physiopathologie et Epidémiologie de l'Insuffisance Respiratoire, Paris, France.
Nassima
N
Ferhani
Séverine
S
Letuve
Alexander
A
Kozhich
Olivier
O
Thibaudeau
Martine
M
Grandsaigne
Marielle
M
Maret
Marie-Christine
MC
Dombret
Gary P
GP
Sims
Roland
R
Kolbeck
Anthony J
AJ
Coyle
Michel
M
Aubier
Marina
M
Pretolani
D056151:Airway Remodeling / Q000502:physiology; D001980:Bronchi / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D005260:Female; D005455:Fluorescent Antibody Technique; D005540:Forced Expiratory Flow Rates; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism
D024243:HMGB1 Protein; D053583:Interleukin-1beta; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic