Advanced glycation endproducts and their receptor in different body compartments in COPD.
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by chronic airway inflammation and emphysema, and is caused by exposure to noxious particles or gases, e.g. cigarette smoke. Smoking and oxidative stress lead to accelerated formation and accumulation of advanced glycation end products (AGEs), causing local tissue damage either directly or by binding the receptor for AGEs (RAGE). This study assessed the association of AGEs or RAGE in plasma, sputum, bronchial biopsies and skin with COPD and lung function, and their variance between these body compartments.


METHODS
Healthy smoking and never-smoking controls (n = 191) and COPD patients (n = 97, GOLD stage I-IV) were included. Autofluorescence (SAF) was measured in the skin, AGEs (pentosidine, CML and CEL) and sRAGE in blood and sputum by ELISA, and in bronchial biopsies by immunohistochemistry. eQTL analysis was performed in bronchial biopsies.


RESULTS
COPD patients showed higher SAF values and lower plasma sRAGE levels compared to controls and these values associated with decreased lung function (p <0.001; adjusting for relevant covariates). Lower plasma sRAGE levels significantly and independently predicted higher SAF values (p < 0.001). One SNP (rs2071278) was identified within a region of 50 kB flanking the AGER gene, which was associated with the gene and protein expression levels of AGER and another SNP (rs2071278) which was associated with the accumulation of AGEs in the skin.


CONCLUSIONS
In COPD, AGEs accumulate differentially in body compartments, i.e. they accumulate in the skin, but not in plasma, sputum and bronchial biopsies. The association between lower sRAGE and higher SAF levels supports the hypothesis that the protective mechanism of sRAGE as a decoy-receptor is impaired in COPD.
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.
Susan J M
SJ
Hoonhorst
Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Adèle T
AT
Lo Tam Loi
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.|Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Simon D
SD
Pouwels
University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.|Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Alen
A
Faiz
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.
Eef D
ED
Telenga
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.
Maarten
M
van den Berge
Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Leo
L
Koenderman
Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Jan-Willem J
JW
Lammers
University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.|Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
H Marike
HM
Boezen
University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.|Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Antoon J M
AJ
van Oosterhout
University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.|Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Monique E
ME
Lodewijk
University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.|Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Wim
W
Timens
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713, GZ, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands.
Dirkje S
DS
Postma
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713, GZ, Groningen, The Netherlands. n.h.t.ten.hacken@umcg.nl.|University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands. n.h.t.ten.hacken@umcg.nl.
Nick H T
NH
Ten Hacken
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001980:Bronchi / Q000378:metabolism*; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D009928:Organ Specificity; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood / Q000378:metabolism*; D012867:Skin / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism*; D013183:Sputum / Q000378:metabolism; D014018:Tissue Distribution; D055815:Young Adult
D015415:Biomarkers; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products
Advanged glycation end-products; COPD; RAGE; sRAGE