RAGE: a new frontier in chronic airways disease.
ABSTRACT Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.
- SourceAvailable from: Maria B SukkarAmerican Journal of Respiratory and Critical Care Medicine 10/2013; 188(8):893-894. · 11.04 Impact Factor
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ABSTRACT: Rationale: Hypoxia regulates the inflammatory/anti-inflammatory balance via the receptor for advanced glycation end products (RAGE), a versatile sensor of damage-associated molecular patterns. The multi-ligand nature of RAGE places this receptor in the midst of chronic inflammatory diseases. Objective: To characterize the impact of the hypoxia/RAGE pathway on pathogenic airway inflammation preventing effective pathogen clearance in Cystic Fibrosis (CF) and elucidate the potential role of this danger signal in pathogenesis and therapy of lung inflammation. Methods: We employed in vivo and in vitro models to study the impact of hypoxia on RAGE expression and activity in human and murine CF, the nature of the RAGE ligand and the impact of RAGE on lung inflammation and antimicrobial resistance in fungal and bacterial pneumonia. Main results: Sustained expression of RAGE and its ligand S100B was observed in murine lung and human epithelial cells and exerted a proximal role in promoting inflammation in murine and human CF, as revealed by functional studies and analysis of the genetic variability of AGER in patients with CF. Both hypoxia and infections contributed to the sustained activation of the S100B/RAGE pathway, being RAGE up-regulated by hypoxia and S100B by infection via Toll-like receptors. Inhibiting the RAGE pathway in vivo with soluble (s)RAGE reduced pathogen load and inflammation in experimental CF while sRAGE production was defective in CF patients. Conclusions: A causal link between hyper-activation of RAGE and inflammation in CF has been observed, such that targeting pathogenic inflammation alleviated inflammation in CF and measurement of sRAGE levels could be a useful biomarker for RAGE-dependent inflammation in CF patients.American Journal of Respiratory and Critical Care Medicine 10/2013; · 11.04 Impact Factor
- American Journal of Respiratory and Critical Care Medicine 12/2013; 188(11):1280-1. · 11.04 Impact Factor