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RAGE/NF-κB Pathway Mediates Lipopolysaccharide-Induced Inflammation in Alveolar Type I Epithelial Cells Isolated from Neonate Rats

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Abstract

Alveolar type I epithelial cells (AECIs) play an important role in the pathogenesis of acute lung injury. The receptor for advanced glycation end-products (RAGEs) is expressed at a high basal level in AECIs, and its soluble isoform is suggested as a marker of AECI injury. However, the molecular mechanism by which RAGE mediates inflammatory injury in AECIs remains elusive. In this study, we established lipopolysaccharide (LPS)-induced inflammation in AECIs isolated from neonate rats as the experimental model and investigated the role of RAGE/NF-κB signaling in mediating inflammatory response in AECIs. We found that LPS increased RAGE expression and the secretion of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in AECIs in a dose-dependent manner. Knockdown of RAGE significantly decreased TNF-α and IL-1β levels in conditioned medium of AECIs. Electrophoretic mobility shift assay (EMSA) showed that NF-κB activation was increased in AECIs treated by LPS. However, knockdown of RAGE inhibited both basic and LPS-induced NF-κB activity in AECIs. Finally, NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) significantly reduced LPS-induced upregulation of RAGE expression at both protein and messenger RNA (mRNA) levels in AECIs. Our results suggest that RAGE mediates inflammatory response in AECIs via activating NF-κB, and RAGE/NF-κB pathway presents potential target for the prevention and therapy of acute lung injury.

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References

  1. Willson, D.F., P.R. Chess, and R.H. Notter. 2008. Surfactant for pediatric acute lung injury. Pediatric Clinics of North America 55: 545–575.

    Article  PubMed  Google Scholar 

  2. Folkesson, H.G., and M.A. Matthay. 2006. Alveolar epithelial ion and fluid transport: recent progress. American Journal of Respiratory Cell and Molecular Biology 35: 10–19.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Matthay, M.A., L. Robriquet, and X. Fang. 2005. Alveolar epithelium: role in lung fluid balance and acute lung injury. Proceedings of the American Thoracic Society 2: 206–213.

    Article  PubMed  CAS  Google Scholar 

  4. Wang, Y., J. Shan, W. Yang, H. Zheng, and S. Xue. 2013. High mobility group box 1 (HMGB1) mediates high-glucose-induced calcification in vascular smooth muscle cells of saphenous veins. Inflammation 36: 1592–1604.

    Article  PubMed  CAS  Google Scholar 

  5. Baek, G.H., Y.S. Jang, S.I. Jeong, J. Cha, M. Joo, S.W. Shin, K.T. Ha, and H.S. Jeong. 2012. Rehmannia glutinosa suppresses inflammatory responses elicited by advanced glycation end products. Inflammation 35: 1232–1241.

    Article  PubMed  Google Scholar 

  6. Buckley, S.T., and C. Ehrhardt. 2010. The receptor for advanced glycation end products (RAGE) and the lung. Journal of Biomedicine and Biotechnology 2010: 917108.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Uchida, T., M. Shirasawa, L.B. Ware, K. Kojima, Y. Hata, K. Makita, G. Mednick, Z.A. Matthay, and M.A. Matthay. 2006. Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. American Journal of Respiratory and Critical Care Medicine 173: 1008–1015.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Tian, Z., Y. Li, P. Ji, S. Zhao, and H. Cheng. 2013. Mesenchymal stem cells protects hyperoxia-induced lung injury in newborn rats via inhibiting receptor for advanced glycation end-products/nuclear factor κB signaling. Experimental Biology and Medicine (Maywood, N.J.) 238: 242–247.

    Article  CAS  Google Scholar 

  9. Tillema, M.S., K.L. Lorenz, M.G. Weiss, et al. 2000. Sublethal endotoxemia promotes pulmonary cytokine-induced neutrophil chemoattractant expression and neutrophil recruitment but not overt lung injury in neonatal rats. Biology of the Neonate 78: 308–314.

    Article  PubMed  CAS  Google Scholar 

  10. Sakurai, R., P. Villarreal, S. Husain, J. Liu, T. Sakurai, E. Tou, J.S. Torday, and V.K. Rehan. 2013. Curcumin protects the developing lung against long-term hyperoxic injury. American Journal of Physiology - Lung Cellular and Molecular Physiology 305: L301–L311.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Chen, J., Z. Chen, T. Narasaraju, N. Jin, and L. Liu. 2004. Isolation of highly pure alveolar epithelial type I and type II cells from rat lungs. Laboratory Investigation 84: 727–735.

    Article  PubMed  Google Scholar 

  12. Tam, A.B., E.L. Mercado, A. Hoffmann, and M. Niwa. 2012. ER stress activates NF-κB by integrating functions of basal IKK activity, IRE1 and PERK. PLoS One 7: e45078.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Downs, C.A., D.W. Montgomery, and C.J. Merkle. 2011. Cell culture models using rat primary alveolar type I cells. Pulmonary Pharmacology & Therapeutics 24: 577–586.

    Article  CAS  Google Scholar 

  14. Lizotte, P.P., L.E. Hanford, J.J. Enghild, E. Nozik-Grayck, B.L. Giles, and T.D. Oury. 2007. Developmental expression of the receptor for advanced glycation end-products (RAGE) and its response to hyperoxia in the neonatal rat lung. BMC Developmental Biology 7: 15.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Shirasawa, M., N. Fujiwara, S. Hirabayashi, H. Ohno, J. Iida, K. Makita, and Y. Hata. 2004. Receptor for advanced glycation end-products is a marker of type I lung alveolar cells. Genes to Cells 9: 165–174.

    Article  PubMed  CAS  Google Scholar 

  16. Ni, Y.F., T. Jiang, Q.S. Cheng, Z.P. Gu, Y.F. Zhu, Z.P. Zhang, J. Wang, X.L. Yan, W.P. Wang, C.K. Ke, Y. Han, and X.F. Li. 2012. Protective effect of magnolol on lipopolysaccharide-induced acute lung injury in mice. Inflammation 35: 1860–1866.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang, L., R. Postina, and Y. Wang. 2009. Ectodomain shedding of the receptor for advanced glycation end products: a novel therapeutic target for Alzheimer’s disease. Cellular and Molecular Life Sciences 66: 3923–3935.

    Article  PubMed  CAS  Google Scholar 

  18. Zhang, H., S. Tasaka, Y. Shiraishi, K. Fukunaga, W. Yamada, H. Seki, Y. Ogawa, K. Miyamoto, Y. Nakano, N. Hasegawa, T. Miyasho, I. Maruyama, and A. Ishizaka. 2008. Role of soluble receptor for advanced glycation end products on endotoxin-induced lung injury. American Journal of Respiratory and Critical Care Medicine 178: 356–362.

    Article  PubMed  CAS  Google Scholar 

  19. Reynolds, P.R., K.M. Wasley, and C.H. Allison. 2011. Diesel particulate matter induces receptor for advanced glycation end-products (RAGE) expression in pulmonary epithelial cells and RAGE signaling influences NF-κB -mediated Inflammation. Environmental Health Perspectives 119: 332–336.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Reynolds, P.R., S.D. Kasteler, R.E. Schmitt, and J.R. Hoidal. 2011. RAGE signals through Ras during tobacco smoke-induced pulmonary inflammation. American Journal of Respiratory Cell and Molecular Biology 45: 411–418.

    Article  PubMed  CAS  Google Scholar 

  21. Wang, M., T. Liu, D. Wang, Y. Zheng, X. Wang, and J. He. 2011. Therapeutic effects of pyrrolidine dithiocarbamate on acute lung injury in rabbits. Journal of Translational Medicine 9: 61.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by the Talent Fund of Huai’an First Hospital, Nanjing Medical University.

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Authors and Affiliations

  1. Department of Neonatology, Huai’an First People’s Hospital, Nanjing Medical University, 6 Beijing Road West, Huai’an, 223300, Jiangsu, People’s Republic of China

    Yuhong Li, Sai Zhao, Huaipin Cheng, Ping Ji, Min Yu & Zhaofang Tian

  2. Neonatal Medical Center, Huai’an Maternity and Child Health Care Hospital, Huai’an, 223002, Jiangsu, People’s Republic of China

    Rong Wu

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  1. Yuhong Li
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  2. Rong Wu
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  3. Sai Zhao
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  4. Huaipin Cheng
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  5. Ping Ji
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  6. Min Yu
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  7. Zhaofang Tian
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Correspondence to Zhaofang Tian.

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Yuhong Li and Rong Wu contributed equally.

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Li, Y., Wu, R., Zhao, S. et al. RAGE/NF-κB Pathway Mediates Lipopolysaccharide-Induced Inflammation in Alveolar Type I Epithelial Cells Isolated from Neonate Rats. Inflammation 37, 1623–1629 (2014). https://doi.org/10.1007/s10753-014-9889-y

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  • DOI: https://doi.org/10.1007/s10753-014-9889-y

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