Receptor for advanced glycation end products and soluble receptor for advanced glycation end products: A balancing act in chronic obstructive pulmonary disease?

American Thoracic Society
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Journal Article
American Journal of Respiratory and Critical Care Medicine, 2013, 188 (8), pp. 893 - 894
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The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor implicated in immune/inflammatory and tissue remodeling responses in numerous pathological states. RAGE plays an important role in lung development during embryogenesis and homeostatic maintenance of the adult lung, where its expression is high relative to other organ tissues (1, 2). RAGE exists primarily in two forms, a transmembrane protein consisting of a cytoplasmic signaling domain and an extracellular ligand-binding domain, and a soluble protein that lacks the transmembrane and cytoplasmic domains. Soluble RAGE (sRAGE) circulates in blood under physiological conditions and is an endogenous inhibitor of RAGE signaling. Although sRAGE is primarily generated through alternative RNA splicing, soluble isoforms are also produced via proteolytic ectodomain shedding of the cell-bound receptor (1). Recent evidence suggests that levels of RAGE expression and sRAGE isoforms are altered in chronic obstructive pulmonary disease (COPD) (1). Higher RAGE expression is observed in epithelial and smooth muscle layers of the airway wall in subjects with COPD than in smokers and never-smokers without COPD (1). In addition, RAGE expression is higher in alveolar walls of resection tissue samples of subjects with than without COPD (3). On the other hand, we and others have demonstrated reduced airway and systemic levels of sRAGE in subjects with COPD, and shown this to be associated with the degree of lung function impairment, predominance of neutrophilic lung inflammation, and both the presence and progression of emphysema (1, 4-6). Boschetto and colleagues did not observe reduced plasma sRAGE in subjects with mild-to-moderate COPD, further suggesting that sRAGE deficiency is associated with more severe disease and/ or disease progression (7).
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