TABLE 1.

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

First author, year [ref]	Country	Population/exposure /design	Study size (number of subjects)	Specimen/assay	End-points	Significant findings
Caraher, 2017 [6]	USA	FDNY, WTC-PM, case cohort	185	Serum/Luminex	FEV1	Odds 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]	Taiwan	COPD, PM10, retrospective case–control	58	Serum, ELISA	FVC, 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]	USA	COPD, cigarette smoke, longitudinal	82	Lung, IHC	UACR, eGFR, AGE-RAGE in pulmonary/renal ECs	↑immunostaining of AGE and RAGE in ECs of COPD cases
Hoonhorst, 2016 [43]	The Netherlands	COPD, cigarette smoke, longitudinal	288	blood/sputum/bronchial biopsies, ELISA/IHC	AGE, sRAGE, lung function	Low sRAGE is associated with COPD and impaired lung function
John, 2016 [44]	UK	COPD, cigarette smoke, cross-sectional	291	Blood, IHC	PWV, BP, skin autofluorescence, sRAGE, lipids	Cardiovascular risk prediction score and sRAGE levels were the same COPD and non-COPD smokers
Carolan, 2014 [45]	USA	COPDGene, cigarette smoke, cross-sectional	588	Plasma, custom assay by Myriad-RBM	%LAA, LP15A, sRAGE	Patients with more emphysema had lower sRAGE and ICAM1 levels
Iwamoto, 2014 [46]	Finland	COPD, cigarette smoke, longitudinal	295	Plasma	FEV1, FVC, FEV1/FVC, sRAGE	Lower sRAGE predicts greater progression of airflow obstruction
Chen, 2014 [47]	China	COPD, cigarette smoke, ex-vivo	40	Lung, HBE/ IHC/ELISA/Western blot	FEV1, FVC, FEV1/FVC, RAGE, NO generation	Overexpression of RAGE contributes to smoking-induced NO generation in COPD
Coxson, 2013 [48]	Multiple	ECLIPSE, cigarette smoke, longitudinal	1285	Serum, ELISA	Lung density on CT scan	Elevated sRAGE, fibrinogen and IL-6 levels at baseline were associated with less progression of emphysema
Cockayne, 2012 [49]	Germany	COPD, cigarette smoke, prospective observational study	185	Serum, 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]	Italy	COPD, cigarette smoke, case–control	401	Plasma, ELISA	FEV1, FEV1/FVC, DLCO, emphysema severity, sRAGE	sRAGE 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]	Finland	IPF/UIP/COPD/AAT	49	Lung, 2-dimensional electrophoresis, mass spectrometry, Western blot, ELISA	RAGE	Three 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]	France	COPD, cigarette smoke, N/A	70	Lung, Western blot, ELISA, Luminex, IHC, BAL, EC, AM	HMGB1, IL-1β, RAGE	Elevated HMGB1 expression in COPD airways may sustain inflammation and remodelling through its interaction with IL-1β and RAGE
Zhang, 2014 [52]	China	COPD, cigarette smoke, N/A	102	Plasma/serum, ELISA	FEV1, FEV1/FVC, HMGB1, sRAGE, hsCRP, fibrinogen	HMGB1 and sRAGE levels were dynamically changed between exacerbation and convalescence phases of COPD
Boschetto, 2013 [53]	Italy	COPD, CHF, COPD + CHF, cigarette smoke, N/A	143	Plasma, ELISA	sRAGE, CML, BNP	Plasma levels of sRAGE and CML are increased in CHF, but not COPD patients
Cho, 2015 [54]	Multiple	COPDGene, ECLIPSE, NETT, GenKOLS, cigarette smoke, N/A	12 031	GWAS	Loci associated with emphysema	The AGER locus was related to an emphysematous phenotype
Hardin, 2012 [55]	Poland	COPD, cigarette smoke, N/A	645	Blood, 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]	China	COPD, cigarette smoke, N/A	455	WBC genomic DNA/ PCR-RFLP	FEV1, FVC, FEV1/FVC	G82S 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]	UK	COPD, cigarette smoke, N/A	992	Lung/serum, IHC, PCR, ELISA	Alveolar 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; D_LCO: diffusing capacity of the lung for carbon monoxide; ΔS_aO2: 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.