Advanced glycation endproducts and their receptor in different body compartments in COPD

Susan J M Hoonhorst, Adèle T Lo Tam Loi, Simon D Pouwels, Alen Faiz, Eef D Telenga, Maarten van den Berge, Leo Koenderman, Jan-Willem J Lammers, H Marike Boezen, Antoon J M van Oosterhout, Monique E Lodewijk, Wim Timens, Dirkje S Postma, Nick H T Ten Hacken, Susan J M Hoonhorst, Adèle T Lo Tam Loi, Simon D Pouwels, Alen Faiz, Eef D Telenga, Maarten van den Berge, Leo Koenderman, Jan-Willem J Lammers, H Marike Boezen, Antoon J M van Oosterhout, Monique E Lodewijk, Wim Timens, Dirkje S Postma, Nick H T Ten Hacken

Abstract

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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00807469 NCT00848406 NCT00850863.

Keywords: Advanged glycation end-products; COPD; RAGE; sRAGE.

Figures

Fig. 1
Fig. 1
The expression of AGEs in plasma, sputum, bronchial biopsies and the skin. The levels of AGEs in a plasma, b sputum, c bronchial biopsies and d skin (SAF). Horizontal lines represent median values with interquartile ranges, * p < 0.05 between groups
Fig. 2
Fig. 2
RAGE expression in plasma, sputum and bronchial biopsies. RAGE levels in a plasma, b sputum, and c bronchial biopsies. Horizontal lines represent median values with interquartile ranges, * p < 0.05 between groups
Fig. 3
Fig. 3
Associations between sRAGE and SAF. Rho = correlation coefficient, SAF = skin autofluorescence, sRAGE is soluble receptor for advanced glycation endproducts. Association after adjustment for age, gender, packyears, BMI, LDL cholesterol and triglycerides was in B = 0.00, p = <0.01
Fig. 4
Fig. 4
Associations of DLCO% predicted with (a) plasma sRAGE levels and (b) skin autofluorescence. All participants from the study were added, including young healthy controls, old healthy controls and COPD patients. Significance was tested using a linear regression analysis. Dotted lines indicate the 95 % confidence intervals
Fig. 5
Fig. 5
Genetic regulation of AGER gene expression levels, RAGE protein levels in sputum and AGE levels in skin. a Expression QTL analysis and b Protein QTL analysis of the AGER gene expression in bronchial biopsies and levels of soluble RAGE in sputum, respectively. SNP association study with AGE levels detected in the skin with c rs915895 and d rs2071278

References

    1. Cerami C, Founds H, Nicholl I, Mitsuhashi T, Giordano D, Vanpatten S, Lee A, Al-Abed Y, Vlassara H, Bucala R, Cerami A. Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci U S A. 1997;94:13915–20. doi: 10.1073/pnas.94.25.13915.
    1. Nicholl ID, Stitt AW, Moore JE, Ritchie AJ, Archer DB, Bucala R. Increased levels of advanced glycation endproducts in the lenses and blood vessels of cigarette smokers. Mol Med. 1998;4:594–601.
    1. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014;18:1–14. doi: 10.4196/kjpp.2014.18.1.1.
    1. Monnier VM, Mustata GT, Biemel KL, Reihl O, Lederer MO, Zhenyu D, Sell DR. Cross-linking of the extracellular matrix by the maillard reaction in aging and diabetes: an update on “a puzzle nearing resolution”. Ann N Y Acad Sci. 2005;1043:533–44. doi: 10.1196/annals.1333.061.
    1. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 2005;83:876–86. doi: 10.1007/s00109-005-0688-7.
    1. Buckley ST, Ehrhardt C. The receptor for advanced glycation end products (RAGE) and the lung. J Biomed Biotechnol. 2010;2010:917108. doi: 10.1155/2010/917108.
    1. Castaldi PJ, Cho MH, Litonjua AA, Bakke P, Gulsvik A, Lomas DA, Anderson W, Beaty TH, Hokanson JE, Crapo JD, Laird N, Silverman EK, COPDGene and Eclipse Investigators The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility. Am J Respir Cell Mol Biol. 2011;45:1147–53. doi: 10.1165/rcmb.2011-0055OC.
    1. Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, Zhao JH, Ramasamy A, Zhai G, Vitart V, Huffman JE, Igl W, Albrecht E, Deloukas P, Henderson J, Granell R, McArdle WL, Rudnicka AR, Wellcome Trust Case Control Consortium. Barroso I, Loos RJF, Wareham NJ, Mustelin L, Rantanen T, Surakka I, Imboden M, Wichmann HE, Grkovic I, Jankovic S, Zgaga L, et al. Genome-wide association study identifies five loci associated with lung function. Nat Genet. 2010;42:36–44. doi: 10.1038/ng.501.
    1. Wu L, Ma L, Nicholson LFB, Black PN. Advanced glycation end products and its receptor (RAGE) are increased in patients with COPD. Respir Med. 2011;105:329–36. doi: 10.1016/j.rmed.2010.11.001.
    1. Ferhani N, Letuve S, Kozhich A, Thibaudeau O, Grandsaigne M, Maret M, Dombret M-C, Sims GP, Kolbeck R, Coyle AJ, Aubier M, Pretolani M. Expression of high-mobility group box 1 and of receptor for advanced glycation end products in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:917–27. doi: 10.1164/rccm.200903-0340OC.
    1. Pouwels SD, Nawijn MC, Bathoorn E, Riezebos-Brilman A, van Oosterhout AJM, Kerstjens HAM, Heijink IH. Increased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients. Eur Respir J. 2015;45:1482–5. doi: 10.1183/09031936.00158.
    1. Pouwels SD, Heijink IH, ten Hacken NHT, Vandenabeele P, Krysko DV, Nawijn MC, van Oosterhout AJM. DAMPs activating innate and adaptive immune responses in COPD. Mucosal Immunol. 2014;7:215–26. doi: 10.1038/mi.2013.77.
    1. Cheng DT, Kim DK, Cockayne DA, Belousov A, Bitter H, Cho MH, Duvoix A, Edwards LD, Lomas DA, Miller BE, Reynaert N, Tal-Singer R, Wouters EFM, Agustí A, Fabbri LM, Rames A, Visvanathan S, Rennard SI, Jones P, Parmar H, MacNee W, Wolff G, Silverman EK, Mayer RJ, Pillai SG, TESRA and ECLIPSE Investigators Systemic soluble receptor for advanced glycation endproducts is a biomarker of emphysema and associated with AGER genetic variants in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;188:948–57. doi: 10.1164/rccm.201302-0247OC.
    1. Gopal P, Rutten EPA, Dentener MA, Wouters EFM, Reynaert NL. Decreased plasma sRAGE levels in COPD: influence of oxygen therapy. Eur J Clin Invest. 2012;42:807–14. doi: 10.1111/j.1365-2362.2012.02646.x.
    1. Iwamoto H, Gao J, Koskela J, Kinnula V, Kobayashi H, Laitinen T, Mazur W. Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap. Eur Respir J. 2014;43:421–9. doi: 10.1183/09031936.00024313.
    1. Miniati M, Monti S, Basta G, Cocci F, Fornai E, Bottai M. Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case-control study. Respir Res. 2011;12:37. doi: 10.1186/1465-9921-12-37.
    1. Smith DJ, Yerkovich ST, Towers MA, Carroll ML, Thomas R, Upham JW. Reduced soluble receptor for advanced glycation end-products in COPD. Eur Respir J. 2011;37:516–22. doi: 10.1183/09031936.00029310.
    1. Hoonhorst SJM, Lo Tam Loi AT, Hartman JE, Telenga ED, van den Berge M, Koenderman L, Lammers JWJ, Boezen HM, Postma DS, Ten Hacken NHT. Advanced glycation end products in the skin are enhanced in COPD. Metabolism. 2014;63:1149–56. doi: 10.1016/j.metabol.2014.06.006.
    1. Gopal P, Reynaert NL, Scheijen JLJM, Engelen L, Schalkwijk CG, Franssen FME, Wouters EFM, Rutten EPA. Plasma advanced glycation end-products and skin autofluorescence are increased in COPD. Eur Respir J. 2014;43:430–8. doi: 10.1183/09031936.00135312.
    1. Lo Tam Loi AT, Hoonhorst SJM, Franciosi L, Bischoff R, Hoffmann RF, Heijink I, van Oosterhout AJM, Boezen HM, Timens W, Postma DS, Lammers J-W, Koenderman L, Ten Hacken NHT. Acute and chronic inflammatory responses induced by smoking in individuals susceptible and non-susceptible to development of COPD: from specific disease phenotyping towards novel therapy. Protocol of a cross-sectional study. BMJ Open. 2013;3.
    1. Meerwaldt R, Links T, Graaff R, Thorpe SR, Baynes JW, Hartog J, Gans R, Smit A. Simple noninvasive measurement of skin autofluorescence. Ann N Y Acad Sci. 2005;1043:290–8. doi: 10.1196/annals.1333.036.
    1. Meerwaldt R, Graaff R, Oomen PHN, Links TP, Jager JJ, Alderson NL, Thorpe SR, Baynes JW, Gans ROB, Smit AJ. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia. 2004;47:1324–30. doi: 10.1007/s00125-004-1451-2.
    1. Kodama T, Kanazawa H, Tochino Y, Kyoh S, Asai K, Hirata K. A technological advance comparing epithelial lining fluid from different regions of the lung in smokers. Respir Med. 2009;103:35–40. doi: 10.1016/j.rmed.2008.09.004.
    1. Rawlins EL, Hogan BLM. Epithelial stem cells of the lung: privileged few or opportunities for many? Development. 2006;133:2455–65. doi: 10.1242/dev.02407.
    1. Annoni R, Lanças T, Yukimatsu Tanigawa R, de Medeiros Matsushita M, de Morais Fernezlian S, Bruno A, Fernando Ferraz da Silva L, Roughley PJ, Battaglia S, Dolhnikoff M, Hiemstra PS, Sterk PJ, Rabe KF, Mauad T. Extracellular matrix composition in COPD. Eur Respir J. 2012;40:1362–73. doi: 10.1183/09031936.00192611.
    1. Boschetto P, Campo I, Stendardo M, Casimirri E, Tinelli C, Gorrini M, Ceconi C, Fucili A, Potena A, Papi A, Ballerin L, Fabbri LM, Luisetti M. Plasma sRAGE and N-(carboxymethyl) lysine in patients with CHF and/or COPD. Eur J Clin Invest. 2013;43:562–9. doi: 10.1111/eci.12079.
    1. Uribarri J, Cai W, Sandu O, Peppa M, Goldberg T, Vlassara H. Diet-derived advanced glycation end products are major contributors to the body’s AGE pool and induce inflammation in healthy subjects. Ann N Y Acad Sci. 2005;1043:461–6. doi: 10.1196/annals.1333.052.
    1. Kanazawa H, Kodama T, Asai K, Matsumura S, Hirata K. Increased levels of N(epsilon)-(carboxymethyl)lysine in epithelial lining fluid from peripheral airways in patients with chronic obstructive pulmonary disease: a pilot study. Clin Sci (Lond) 2010;119:143–9. doi: 10.1042/CS20100096.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться