TABLE 1

Relevance of the receptor for advanced glycation end-products (RAGE) in obstructive airways disease secondary to environmental exposure

First author, year [ref]CountryPopulation/exposure /designStudy size (number of subjects)Specimen/assayEnd-pointsSignificant findings
Caraher, 2017 [6]USAFDNY, WTC-PM, case cohort185Serum/LuminexFEV1Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with sRAGE ≥97 pg·mL−1, CRP ≥2.4 mg·L−1 and MMP-9 ≤397 ng·mL−1, respectively
Lee, 2016 [41]TaiwanCOPD, PM10, retrospective case–control58Serum, ELISAFVC, FEV1/FVC, RV/TLC, DLCO, ΔSaO2,
8-isoprostane,
IL-6, RAGE, carbonyl oxidation, ubiquitin, proteasome, beclin-1
Exposure to elevated levels of PM10 was associated with reduced circulating RAGE levels
Polverino, 2017 [42]USACOPD, cigarette smoke, longitudinal82Lung,
IHC
UACR, eGFR,
AGE-RAGE in pulmonary/renal ECs
↑immunostaining of AGE and RAGE in ECs of COPD cases
Hoonhorst, 2016 [43]The NetherlandsCOPD, cigarette smoke, longitudinal288blood/sputum/bronchial biopsies, ELISA/IHCAGE, sRAGE,
lung function
Low sRAGE is associated with COPD and impaired lung function
John, 2016 [44]UKCOPD, cigarette smoke, cross-sectional291Blood, IHCPWV, BP, skin autofluorescence, sRAGE, lipidsCardiovascular risk prediction score and sRAGE levels were the same COPD and non-COPD smokers
Carolan, 2014 [45]USACOPDGene, cigarette smoke, cross-sectional588Plasma, custom assay by Myriad-RBM%LAA, LP15A, sRAGEPatients with more emphysema had lower sRAGE and ICAM1 levels
Iwamoto, 2014 [46]FinlandCOPD, cigarette smoke, longitudinal295PlasmaFEV1, FVC, FEV1/FVC, sRAGELower sRAGE predicts greater progression of airflow obstruction
Chen, 2014 [47]ChinaCOPD, cigarette smoke, ex-vivo40Lung, HBE/ IHC/ELISA/Western blotFEV1, FVC, FEV1/FVC, RAGE,
NO generation
Overexpression of RAGE contributes to smoking-induced NO generation in COPD
Coxson, 2013 [48]MultipleECLIPSE, cigarette smoke, longitudinal1285Serum, ELISALung density on CT scanElevated sRAGE, fibrinogen and IL-6 levels at baseline were associated with less progression of emphysema
Cockayne, 2012 [49]GermanyCOPD, cigarette smoke, prospective observational study185Serum,
multiplex
FEV1, FEV1/FVC,
DLCO, 142 analytes
sRAGE and EN-RAGE were two out of seven biomarkers that showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and nonsmoking control groups; sRAGE and EN-RAGE affect different lung function measures
Miniati, 2011 [50]ItalyCOPD,
cigarette smoke,
case–control
401Plasma,
ELISA
FEV1, FEV1/FVC, DLCO, emphysema severity, sRAGEsRAGE is significantly lower in patients with COPD than in age- and sex-matched individuals without obstruction
Emphysema is an independent predictor of reduced sRAGE in COPD
Ohlmeier, 2010 [51]FinlandIPF/UIP/COPD/AAT49Lung,
2-dimensional electrophoresis, mass spectrometry, Western blot, ELISA
RAGEThree RAGE variants (FL-RAGE, cRAGE, esRAGE) are important in IPF. The decline of FL-RAGE and cRAGE, but not esRAGE, in COPD lungs is evidence of the involvement of specific RAGE variants in this disease
Ferhani, 2010 [18]FranceCOPD,
cigarette smoke, N/A
70Lung,
Western blot, ELISA, Luminex, IHC, BAL, EC, AM
HMGB1, IL-1β, RAGEElevated HMGB1 expression in COPD airways may sustain inflammation and remodelling through its interaction with IL-1β and RAGE
Zhang, 2014 [52]ChinaCOPD,
cigarette smoke, N/A
102Plasma/serum, ELISAFEV1, FEV1/FVC, HMGB1, sRAGE, hsCRP, fibrinogenHMGB1 and sRAGE levels were dynamically changed between exacerbation and convalescence phases of COPD
Boschetto, 2013 [53]ItalyCOPD, CHF, COPD + CHF, cigarette smoke, N/A143Plasma,
ELISA
sRAGE, CML, BNPPlasma levels of sRAGE and CML are increased in CHF, but not COPD patients
Cho, 2015 [54]MultipleCOPDGene, ECLIPSE, NETT, GenKOLS, cigarette smoke, N/A12 031GWASLoci associated with emphysemaThe AGER locus was related to an emphysematous phenotype
Hardin, 2012 [55]PolandCOPD,
cigarette smoke, N/A
645Blood,
TaqMan
FEV1, FEV1/FVC, SNPs
COPD and COPD-associated phenotypes, SNPs previously associated with lung function in GWAS and COPD were assessed
In patients with severe COPD, there is an association between two SNPs previously associated with COPD (CHRNA3/5 and IREB2), as well as an association with COPD of one locus initially associated with lung function (ADCY2)
Li, 2014 [56]ChinaCOPD,
cigarette smoke, N/A
455WBC genomic DNA/ PCR-RFLPFEV1, FVC, FEV1/FVCG82S polymorphism in the RAGE gene is associated with increased risk of COPD; GS genotype of the G82S variant is a COPD risk factor
Miller, 2016 [57]UKCOPD,
cigarette smoke, N/A
992Lung/serum, IHC, PCR, ELISAAlveolar RAGE,
AGER splicing, sRAGE
AGER splicing, Ser82 allele associated with increased FEV1 and FEV1/FVC ratio and decreased sRAGE

FDNY: Fire Department of New York; WTC-PM: World Trade Center-particulate matter; FEV1: forced expiratory volume in 1 s; WTC-LI: WTC lung injury; sRAGE: soluble RAGE; CRP: C-reactive protein; MMP: matrix metalloproteinase; COPD: chronic obstructive pulmonary disease; PM10: particulate matter <10 µm in aerodynamic diameter; FVC: forced vital capacity; RV: residual volume; TLC: total lung capacity; DLCO: diffusing capacity of the lung for carbon monoxide; ΔSaO2: change in arterial oxygen saturation; IL: interleukin; IHC: immunohistochemistry; UACR: urinary albumin/creatinine ratio; eGFR: estimated glomerular filtration rate; AGE: advanced glycation end-products; EC: endothelial cells; PWV: pulse wave velocity; BP: blood pressure; %LAA: percentage low lung attenuation; LP15A: 15th percentile on lung attenuation curve; ICAM: intercellular adhesion molecule; HBE: human bronchial epithelial cells; NO: nitric oxide; ECLIPSE: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; CT: computed tomography; EN-RAGE: extracellular RAGE-binding protein; IPF: idiopathic pulmonary fibrosis; UIP: usual interstitial pneumonia; AAT: α1-antitrypsin; FL-RAGE: full-length RAGE; cRAGE: C-terminal processed RAGE; esRAGE: endogenous secretory RAGE; N/A: not applicable; BAL: bronchoalveolar lavage; AM: alveolar macrophages; HMGB: high mobility group box; hsCRP: high-sensitivity CRP; CHF: congestive heart failure; CML: N-(carboxymethyl) lysine adducts; BNP: brain natriuretic peptide; NETT: National Emphysema Treatment Trial; GenKOLS: Genetics of Chronic Obstructive Lung Disease; GWAS: genome-wide association studies; AGER: advanced glycation end-products receptor; SNP: single nucleotide polymorphism; CHRNA: cholinergic receptor nicotinic α1 subunit; IREB: iron-responsive element-binding protein; ADCY: adenylate cyclase; WBC: white blood cell count; RFLP: restriction fragment length polymorphism.