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Overexpression of RAGE Contributes to Cigarette Smoke-Induced Nitric Oxide Generation in COPD

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Abstract

Background

Receptor for advanced glycation end products (RAGE), a multiple-ligands receptor, is implicated in chronic obstructive pulmonary disease (COPD). This study was designed to investigate the potential role of RAGE in nitric oxide (NO) generation, an endogenous marker of nitrosative stress in COPD.

Methods

Lung tissues from COPD patients were used to describe the relationship between RAGE expression and NO level. RAGE expression was assessed by immunohistochemistry, western blot, and ELISA. Human bronchial epithelial cells (16HBE) were cultured with cigarette smoke extract (CSE). Neutralizing antibody against RAGE was used to detect the role of RAGE in CSE-induced NO generation by 16HBE cells.

Results

Compared with nonsmoker controls, overexpression of RAGE was significantly detected in COPD smokers (p < 0.01), but not healthy smokers and nonsmokers with COPD, which was dominantly expressed at bronchiolar epithelia. Correlation analysis showed that RAGE in COPD smokers was positively related to NO level, smoking status, and lung function decline. In cultured 16HBE cells treated with CSE, soluble RAGE was reduced; however, full-length RAGE was enhanced significantly as the same trend as NO generation. Moreover, increased NO level and NO synthase activity, decreased total glutathione (a major cellular antioxidant), enhanced nuclear translocation of p65 (a key molecule of nuclear factor (NF)-κB) and release of NF-κB-dependent proinflammatory cytokines were all reversed by pretreatment of anti-RAGE antibody.

Conclusions

These findings suggest that overexpression of RAGE contributes to CS-induced NO generation in COPD with involvement in NF-κB activation.

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References

  1. Ricciardolo FL, Caramori G, Ito K, Capelli A, Brun P, Abatangelo G, Papi A, Chung KF, Adcock I, Barnes PJ, Donner CF, Rossi A, Di Stefano A (2005) Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease. J Allergy Clin Immunol 116:1028–1035

    Article  CAS  PubMed  Google Scholar 

  2. MacNee W (2010) Oxidative stress and chronic obstructive pulmonary disease. Manag Chronic Obstr Pulm Dis 1:100–129

    Google Scholar 

  3. Ramasamy R, Vannucci SJ, Yan SSD, Herold K, Yan SF, Schmidt AM (2005) Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15:16R–28R

    Article  CAS  PubMed  Google Scholar 

  4. Sumi D, Ignarro LJ (2004) Regulation of inducible nitric oxide synthase expression in advanced glycation end product–stimulated RAW 264.7 cells: the role of heme oxygenase-1 and endogenous nitric oxide. Diabetes 53:1841–1850

    Article  CAS  PubMed  Google Scholar 

  5. Rojas A, Figueroa H, Morales E (2010) Fueling inflammation at tumor microenvironment: the role of multiligand/rage axis. Carcinogenesis 31:334–341

    Article  CAS  PubMed  Google Scholar 

  6. He M, Kubo H, Ishizawa K, Hegab AE, Yamamoto Y, Yamamoto H, Yamaya M (2007) The role of the receptor for advanced glycation end-products in lung fibrosis. Am J Physiol Lung Cell Mol Physiol 293:L1427–L1436

    Article  CAS  PubMed  Google Scholar 

  7. Uchida T, Shirasawa M, Ware LB, Kojima K, Hata Y, Makita K, Mednick G, Matthay ZA, Matthay MA (2006) Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med 173:1008–1015

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Morbini P, Villa C, Campo I, Zorzetto M, Inghilleri S, Luisetti M (2006) The receptor for advanced glycation end products and its ligands: a new inflammatory pathway in lung disease? Mod Pathol 19:1437–1445

    CAS  PubMed  Google Scholar 

  9. Wu L, Ma L, Nicholson LF, Black PN (2011) Advanced glycation end products and its receptor (RAGE) are increased in patients with COPD. Respir Med 105:329–336

    Article  PubMed  Google Scholar 

  10. Ferhani N, Letuve S, Kozhich A, Thibaudeau O, Grandsaigne M, Maret M, Dombret M, Sims GP, Kolbeck R, Coyle AJ, Aubier M, Pretolani M (2010) 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 181:917–927

    Article  CAS  PubMed  Google Scholar 

  11. Reynolds PR, Kasteler SD, Schmitt RE, Hoidal JR (2011) Receptor for advanced glycation end-products signals through ras during tobacco smoke-induced pulmonary inflammation. Am J Respir Cell Mol Biol 45:411–418

    Article  CAS  PubMed  Google Scholar 

  12. Vayssier-Taussat M, Camilli T, Aron Y, Meplan C, Hainaut P, Polla BS, Weksler B (2001) Effects of tobacco smoke and benzo[a]pyrene on human endothelial cell and monocyte stress responses. Am J Physiol Heart Circ Physiol 280:H1293–H1300

    CAS  PubMed  Google Scholar 

  13. Tabera S, Pérez-Simón JA, Díez-Campelo M, Sánchez-Abarca LI, Blanco B, López A, Benito A, Ocio E, Sánchez-Guijo FM, Cañizo C, San Miguel JF (2008) The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica 93:1301–1309

    Article  CAS  PubMed  Google Scholar 

  14. Chen L, Wang T, Zhang JY, Zhang SF, Liu DS, Xu D, Wang X, Chen YJ, Wen FQ (2009) Toll-like receptor 4 relates to lipopolysaccharide-induced mucus hypersecretion in rat airway. Arch Med Res 40:10–17

    Article  CAS  PubMed  Google Scholar 

  15. Liu DS, Liu WJ, Chen L, Ou XM, Wang T, Feng YL, Zhang SF, Xu D, Chen YJ, Wen FQ (2009) Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates acrolein-induced airway mucus hypersecretion in rats. Toxicology 260:112–119

    Article  CAS  PubMed  Google Scholar 

  16. Xiong J, Lu H, Lu K, Duan Y, An L, Zhu C (2009) Cadmium decreases crown root number by decreasing endogenous nitric oxide, which is indispensable for crown root primordia initiation in rice seedlings. Planta 230:599–610

    Article  CAS  PubMed  Google Scholar 

  17. Herold K, Moser B, Chen Y, Zeng S, Yan SF, Ramasamy R, Emond J, Clynes R, Schmidt AM (2007) Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress. J Leukoc Biol 82:204–212

    Article  CAS  PubMed  Google Scholar 

  18. Ohlmeier S, Mazur W, Salmenkivi K, Myllärniemi M, Bergmann U, Kinnula VL (2010) Proteomic studies on receptor for advanced glycation end product variants in idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Proteomics Clin Appl 4(1):97–105

    Article  CAS  PubMed  Google Scholar 

  19. Miniati M, Monti S, Basta G, Cocci F, Fornai E, Bottai M (2011) Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case-control study. Respir Res 30(12):37

    Article  Google Scholar 

  20. Smith DJ, Yerkovich ST, Towers MA, Carroll ML, Thomas R, Upham JW (2011) Reduced soluble receptor for advanced glycation end-products in COPD. Eur Respir J 37(3):516–522

    Article  CAS  PubMed  Google Scholar 

  21. Sukkar MB, Wood LG, Tooze M, Simpson JL, McDonald VM, Gibson PG, Wark PA (2012) Soluble RAGE is deficient in neutrophilic asthma and COPD. Eur Respir J 39:721–729

    Article  CAS  PubMed  Google Scholar 

  22. Zhang S, Xu N, Nie J, Dong L, Li J, Tong J (2008) Proteomic alteration in lung tissue of rats exposed to cigarette smoke. Toxicol Lett 178:191–196

    Article  CAS  PubMed  Google Scholar 

  23. Liu Y, Ma Y, Wang R, Xia C, Zhang R, Lian K, Luan R, Sun L, Yang L, Lau WB, Wang H, Tao L (2011) Advanced glycation end products accelerate ischemia/ reperfusion injury through receptor of advanced end product/nitrative thioredoxin inactivation in cardiac microvascular endothelial cells. Antioxid Redox Signal 15:1769–1778

    Article  CAS  PubMed  Google Scholar 

  24. Vincent AM, Perrone L, Sullivan KA, Backus C, Sastry AM, Lastoskie C, Feldman EL (2007) Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. Endocrinology 148:548–558

    Article  CAS  PubMed  Google Scholar 

  25. Kamioka M, Ishibashi T, Ohkawara H, Nagai R, Sugimoto K, Uekita H, Matsui T, Yamagishi S, Ando K, Sakamoto T, Sakamoto N, Takuwa Y, Wada I, Shiomi M, Maruyama Y, Takeishi Y (2011) Involvement of membrane type 1-matrix metalloproteinase (MT1-MMP) in RAGE activation signaling pathways. J Cell Physiol 226:1554–1563

    Article  CAS  PubMed  Google Scholar 

  26. Marshall HE, Merchant K, Stamler JS (2000) Nitrosation and oxidation in the regulation of gene expression. FASEB J 14:1889–1900

    Article  CAS  PubMed  Google Scholar 

  27. Yoshida T, Tuder RM (2007) Pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease. Physiol Rev 87:1047–1082

    Article  CAS  PubMed  Google Scholar 

  28. Chen L, Liu L, Wang T, Shen YC, Wen FQ (2013) Receptor for advanced glycation end products: a new therapeutic target for chronic obstructive pulmonary disease? Arch Med Res 44(1):75–76

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported in part by Grants 81200031, 31000513, 31171103, and 81230001 from the National Natural Science Foundation of China and Grant 06-834 from the China Medical Board of New York.

Conflict of interest

None.

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Authors and Affiliations

  1. Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, China

    Lei Chen, Tao Wang, Lingli Guo, Yongchun Shen, Ting Yang, Chun Wan, Zenglin Liao, Dan Xu & Fuqiang Wen

  2. Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, China

    Lei Chen, Tao Wang, Lingli Guo, Yongchun Shen, Ting Yang, Chun Wan, Zenglin Liao, Dan Xu & Fuqiang Wen

Authors
  1. Lei Chen
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  2. Tao Wang
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  4. Yongchun Shen
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Corresponding author

Correspondence to Fuqiang Wen.

Additional information

Lei Chen, Tao Wang, and Lingli Guo have contributed equally to this study.

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Chen, L., Wang, T., Guo, L. et al. Overexpression of RAGE Contributes to Cigarette Smoke-Induced Nitric Oxide Generation in COPD. Lung 192, 267–275 (2014). https://doi.org/10.1007/s00408-014-9561-1

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  • DOI: https://doi.org/10.1007/s00408-014-9561-1

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