The Role of Receptor for Advanced Glycation End Products in Airway Inflammation in CF and CF related Diabetes

Mulrennan, Siobhain; Baltic, Svetlana; Aggarwal, Shashi; Wood, Jamie; Miranda, Alina; Frost, Felicity; Kaye, Joey; Thompson, Philip J.

doi:10.1038/srep08931

Cited by 40 publications

(38 citation statements)

References 20 publications

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“…sRAGE acts as a decoy of RAGE signaling, thereby inhibiting the interaction between RAGE and proinflammatory ligands (such as HMGB1 and AGEs), which have been proposed to play critical roles in multiple inflammatory diseases [23,29,30]. Low sRAGE levels have been reported in studies of individuals with inflammatory lung diseases, such as COPD [25,31], asthma [32], and cystic fibrosis [33]. Consistent with these findings, we found that serum levels of sRAGE were decreased in patients with silicosis.…”

Section: Discussionsupporting

confidence: 89%

Decreased Soluble Receptor of Advanced Glycation End Product Levels Correlated with Inflammation in Silicosis

Liu

Tian

et al. 2020

Mediators of Inflammation

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Silicosis is a devastating disease caused by inhalation of silica dust that leads to inflammatory cascade and then scarring of the lung tissue. Increasing evidences indicate that soluble receptor for advanced glycation end products (sRAGE) is involved in inflammatory diseases. However, no data on the possible relationship between sRAGE and inflammation of silicosis are available. In this study, serum from subjects with silicosis (n=59) or from healthy controls (HC, n=14) was analyzed for the secretion of sRAGE, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), transforming growth factor-β1 (TGF-β1), and oxidized low-density lipoprotein (ox-LDL). The associations between sRAGE and cytokines and ox-LDL and lung function were assessed by Pearson’s correlation analyses. Mean levels of serum sRAGE were lower in silicosis than those in controls (p<0.05). The subjects who had a longer term of occupational exposure had higher levels of sRAGE (p<0.05). The secretion of TNF-α, IL-1β, IL-6, TGF-β1, and ox-LDL was significantly higher in the silicosis group than that in the HC group (p<0.05). Furthermore, the levels of sRAGE were negatively correlated with TNF-α, IL-6, IL-1β, and ox-LDL. There is no correlation between sRAGE and TGF-β1 and lung function. The optimal point of sRAGE for differentiating silicosis from healthy controls was 14250.02 pg/ml by ROC curve analysis. A decrease in serum sRAGE and its association with inflammatory response might suggest a role for sRAGE in the pathogenesis of silicosis.

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Section: Discussionsupporting

confidence: 89%

Decreased Soluble Receptor of Advanced Glycation End Product Levels Correlated with Inflammation in Silicosis

Liu

Tian

et al. 2020

Mediators of Inflammation

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“…It has been hypothesized that elevated sputum glucose found in CFRD could be a carbon source that would support increased bacterial growth and lead to pulmonary exacerbations. In support of this hypothesis, measured sputum glucose concentrations are very low and often below detection, suggesting glucose is being consumed in the sputum either by infecting microbes or the host inflammatory cells . The glucose concentration in sinus secretions in the context of CFRD has not been described, although similar pathophysiology could be at play.…”

Section: Discussionmentioning

confidence: 99%

Clinical predictors of cystic fibrosis chronic rhinosinusitis severity

Zemke

Nouraie

Moore

et al. 2019

Int Forum Allergy Rhinol

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Background Chronic rhinosinusitis (CRS) is a significant manifestation of cystic fibrosis (CF) with wide‐ranging symptom and disease severity. The goal of the study was to determine clinical variables that correlate with outcome measures of disease severity. Methods A prospective, longitudinal, observational study of 33 adults with symptomatic CRS treated in a CF‐focused otolaryngology clinic was performed. Symptom severity, the presence of rhinosinusitis exacerbations, and endoscopic appearance were assessed, and regression analysis was used to determine clinical predictors of disease outcome. Results Thirty‐three adults with CF‐CRS were included in the study and followed for a mean of 15 months. Rhinosinusitis exacerbations occurred in 61% of participants during the study, and female sex increased the odds of presenting with an exacerbation visit. Sinus disease exacerbations were associated with an odds ratio of 2.07 for presenting with a pulmonary exacerbation at the next visit. CF‐related diabetes was found to be associated with worse symptoms and endoscopic appearance. Infection with Staphylococcus aureus predicted worsening of symptoms, whereas infections with Pseudomonas aeruginosa improved over time. Allergic rhinitis was associated with worse endoscopic appearance, and nasal steroid use was associated with improved endoscopic appearance. Conclusion Sex, CF‐related diabetes, sinonasal infection status, allergic rhinitis, and nasal steroid use may all modulate severity of CF‐CRS in adults. Sinusitis exacerbation may be a precursor to pulmonary exacerbation.

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“…The rationale for blockade of RAGE signal transduction is supported by work in a variety of preclinical disease models such as diabetes and its complications, Alzheimer’s disease 53 54 , cardiovascular disease 42 44 55 56 , immune/inflammatory disorders 57 58 and cancer 59 60 , as examples. RAGE ligands accumulate in these settings and therefore their contribution to the pathogenesis of cellular dysfunction and tissue damage in these diseases may ultimately be mitigated by modulation of RAGE signaling.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction

Manigrasso

Pan

Rai

et al. 2016

Sci Rep

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The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer’s disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI).

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The Role of Receptor for Advanced Glycation End Products in Airway Inflammation in CF and CF related Diabetes

Cited by 40 publications

References 20 publications

Decreased Soluble Receptor of Advanced Glycation End Product Levels Correlated with Inflammation in Silicosis

Decreased Soluble Receptor of Advanced Glycation End Product Levels Correlated with Inflammation in Silicosis

Clinical predictors of cystic fibrosis chronic rhinosinusitis severity

Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction

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