Abstract
Cystic Fibrosis (CF) is often accompanied by diabetes leading to worsening lung function, the reason for which is unclear. The receptor for advanced-glycation-end-products (RAGE) regulates immune responses and inflammation and has been linked to diabetes and possibly CF. We performed a pilot study to determine if CF and CF-related diabetes (CFRD) are associated with enhanced RAGE expression. Full length (fl)RAGE, soluble (s)RAGE, endogenous soluble (es)RAGE, S100A12 (enRAGE) and advanced-glycation-end-products (AGE) expression was assessed in serum, white blood cells and sputum of patients with CF; diabetes; CFRD and healthy subjects. Sputum enRAGE/sRAGE ratios were high in CF but particularly in CFRD which negatively correlated with % predicted FEV1. Serum AGE and AGE/sRAGE ratios were high in diabetics but not in CF. A complex, multifaceted approach was used to assess the role of RAGE and its ligands which is fundamental to determining their impact on airway inflammation. There is a clear association between RAGE activity in the airways of CF and CFRD patients that is not evident in the vascular compartment and correlates with lung function, in contrast to diabetes. This strongly suggests a role for RAGE in contributing to the inflammatory overdrive seen in CF and to a greater extent in CFRD.
Highlights
Cystic Fibrosis (CF) is often accompanied by diabetes leading to worsening lung function, the reason for which is unclear
Down-regulation of both receptor for advanced-glycation-end-products (RAGE) isoforms at the mRNA level was observed in diabetes compared to healthy individuals, (p . 0.05). fl/membrane RAGE (mRAGE) and esRAGE mRNA were overexpressed in CF-related diabetes (CFRD) patients to a lesser extent than in the in sputums of CF only group (p . 0.05) (Fig. 1)
RAGE and RAGE ligands are linked to chronic inflammatory states and we hypothesised that collectively they contribute to the rapid decline in lung function seen in CFRD
Summary
Cystic Fibrosis (CF) is often accompanied by diabetes leading to worsening lung function, the reason for which is unclear. There is a clear association between RAGE activity in the airways of CF and CFRD patients that is not evident in the vascular compartment and correlates with lung function, in contrast to diabetes. This strongly suggests a role for RAGE in contributing to the inflammatory overdrive seen in CF and to a greater extent in CFRD. RAGE binds a broad range of ligands associated with inflammatory responses, including advanced glycation end products (AGE), b-sheet fibrillary structures (b-amyloid & serum amyloid A), amphoterin (HMGB1) and members of the S100/calgranulin family (such as S100A12 known as enRAGE)[3,5,6]. RAGE expression and its signaling are regulated both by its ligands and by RAGE isoforms known collectively as soluble RAGE (sRAGE). sRAGE contains the extracellular domain of RAGE and can bind to circulating proinflammatory ligands preventing their binding to mRAGE thereby preventing RAGE activation. sRAGE consists of a combination of isoforms that are generated in two distinct ways: 1) cleaved RAGE (cRAGE) which results www.nature.com/scientificreports
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