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Mediators of Inflammation
Volume 2015, Article ID 487508, 19 pages
http://dx.doi.org/10.1155/2015/487508
Review Article

Role of Sphingolipids in the Pathobiology of Lung Inflammation

Department of Health Sciences, University of Milan, San Paolo Hospital Medical School, Via Di Rudinì 8, 20142 Milan, Italy

Received 8 August 2015; Revised 24 October 2015; Accepted 27 October 2015

Academic Editor: Ashley Snider

Copyright © 2015 Riccardo Ghidoni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. I. Petrache and D. N. Petrusca, “The involvement of sphingolipids in chronic obstructive pulmonary diseases,” Handbook of Experimental Pharmacology, vol. 216, pp. 247–264, 2013. View at Publisher · View at Google Scholar · View at Scopus
  2. J. Tibboel, I. Reiss, J. C. de Jongste, and M. Post, “Sphingolipids in lung growth and repair,” Chest, vol. 145, no. 1, pp. 120–128, 2014. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Uhlig and Y. Yang, “Sphingolipids in acute lung injury,” Handbook of Experimental Pharmacology, vol. 216, pp. 227–246, 2013. View at Publisher · View at Google Scholar · View at Scopus
  4. Y. Yang and S. Uhlig, “The role of sphingolipids in respiratory disease,” Therapeutic Advances in Respiratory Disease, vol. 5, no. 5, pp. 325–344, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. L. Gluck, E. K. Motoyama, H. L. Smits, and M. V. Kulovich, “The biochemical development of surface activity in mammalian lung. I. The surface-active phospholipids; the separation and distribution of surface-active lecithin in the lung of the developing rabbit fetus,” Pediatric Research, vol. 1, no. 4, pp. 237–246, 1967. View at Publisher · View at Google Scholar · View at Scopus
  6. S. J. Thannhauser, J. Penotti, and N. F. Boncoddo, “Isolation and properties of hydrolecithin (dipalmityl lecithin) from lung; its occurrence in the sphingomyelin fraction of animal tissues,” The Journal of Biological Chemistry, vol. 166, no. 2, pp. 669–675, 1946. View at Google Scholar
  7. L. Gluck, M. V. Kulovich, R. C. Borer Jr., P. H. Brenner, G. G. Anderson, and W. N. Spellacy, “Diagnosis of the respiratory distress syndrome by amniocentesis,” American Journal of Obstetrics and Gynecology, vol. 109, no. 3, pp. 440–445, 1971. View at Google Scholar · View at Scopus
  8. T. A. Doran, J. A. Ford, L. C. Allen, P. Y. Wong, and R. J. Benzie, “Amniotic fluid lecithin/sphingomyelin ratio, palmitic acid, palmitic acid/stearic acid ratio, total cortisol, creatinine, and percentage of lipid-positive cells in assessment of fetal maturity and fetal pulmonary maturity: a comparison,” American Journal of Obstetrics and Gynecology, vol. 133, no. 3, pp. 302–307, 1979. View at Google Scholar · View at Scopus
  9. A. E. Besnard, S. A. M. Wirjosoekarto, K. A. Broeze, B. C. Opmeer, and B. W. J. Mol, “Lecithin/sphingomyelin ratio and lamellar body count for fetal lung maturity: a meta-analysis,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 169, no. 2, pp. 177–183, 2013. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Hallman and L. Gluck, “Formation of acidic phopholipids in rabbit lung during perinatal development,” Pediatric Research, vol. 14, no. 11, pp. 1250–1259, 1980. View at Publisher · View at Google Scholar · View at Scopus
  11. C. A. Longo, D. Tyler, and R. K. Mallampalli, “Sphingomyelin metabolism is developmentally regulated in rat lung,” American Journal of Respiratory Cell and Molecular Biology, vol. 16, no. 5, pp. 605–612, 1997. View at Publisher · View at Google Scholar · View at Scopus
  12. T. A. Lagace and N. D. Ridgway, “The role of phospholipids in the biological activity and structure of the endoplasmic reticulum,” Biochimica et Biophysica Acta, vol. 1833, no. 11, pp. 2499–2510, 2013. View at Publisher · View at Google Scholar · View at Scopus
  13. A. H. Merrill Jr., D. W. Nixon, and R. D. Williams, “Activities of serine palmitoyltransferase (3-ketosphinganine synthase) in microsomes from different rat tissues,” Journal of Lipid Research, vol. 26, no. 5, pp. 617–622, 1985. View at Google Scholar · View at Scopus
  14. A. J. Westover and T. J. M. Moss, “Effects of intrauterine infection or inflammation on fetal lung development,” Clinical and Experimental Pharmacology & Physiology, vol. 39, no. 9, pp. 824–830, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Hallman, “The surfactant system protects both fetus and newborn,” Neonatology, vol. 103, no. 4, pp. 320–326, 2013. View at Publisher · View at Google Scholar · View at Scopus
  16. H. Khammash, M. Perlman, J. Wojtulewicz, and M. Dunn, “Surfactant therapy in full-term neonates with severe respiratory failure,” Pediatrics, vol. 92, no. 1, pp. 135–139, 1993. View at Google Scholar · View at Scopus
  17. R. L. Auten, R. H. Notter, J. W. Kendig, J. M. Davis, and D. L. Shapiro, “Surfactant treatment of full-term newborns with respiratory failure,” Pediatrics, vol. 87, no. 1, pp. 101–107, 1991. View at Google Scholar · View at Scopus
  18. V. Zambelli, G. Bellani, M. Amigoni et al., “The effects of exogenous surfactant treatment in a murine model of two-hit lung injury,” Anesthesia and Analgesia, vol. 120, no. 2, pp. 381–388, 2015. View at Publisher · View at Google Scholar · View at Scopus
  19. M. P. Sherman, J. B. D'Ambola, E. E. Aeberhard, and C. T. Barrett, “Surfactant therapy of newborn rabbits impairs lung macrophage bactericidal activity,” Journal of Applied Physiology, vol. 65, no. 1, pp. 137–145, 1988. View at Google Scholar · View at Scopus
  20. I. Bersani, S. Kunzmann, and C. P. Speer, “Immunomodulatory properties of surfactant preparations,” Expert Review of Anti-Infective Therapy, vol. 11, no. 1, pp. 99–110, 2013. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Nishimura, T. Saida, S. Kuroki et al., “Post-infectious encephalitis with anti-galactocerebroside antibody subsequent to Mycoplasma pneumoniae infection,” Journal of the Neurological Sciences, vol. 140, no. 1-2, pp. 91–95, 1996. View at Publisher · View at Google Scholar · View at Scopus
  22. S. de Bentzmann, P. Roger, and E. Puchelle, “Pseudomonas aeruginosa adherence to remodelling respiratory epithelium,” The European Respiratory Journal, vol. 9, no. 10, pp. 2145–2150, 1996. View at Publisher · View at Google Scholar · View at Scopus
  23. A. J. Ratner, R. Bryan, A. Weber et al., “Cystic fibrosis pathogens activate Ca2+-dependent mitogen-activated protein kinase signaling pathways in airway epithelial cells,” The Journal of Biological Chemistry, vol. 276, no. 22, pp. 19267–19275, 2001. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Gotoh, S. Tsuru, N. Shinomiya et al., “Functional changes of alveolar macrophages in carragheenan-induced aspiration pneumonia model mice,” Natural Immunity, vol. 11, no. 6, pp. 345–355, 1992. View at Google Scholar · View at Scopus
  25. M. M. B. Moreno-Altamirano, I. Aguilar-Carmona, and F. J. Sánchez-García, “Expression of GM1, a marker of lipid rafts, defines two subsets of human monocytes with differential endocytic capacity and lipopolysaccharide responsiveness,” Immunology, vol. 120, no. 4, pp. 536–543, 2007. View at Publisher · View at Google Scholar · View at Scopus
  26. C. Chan and T. Goldkorn, “Ceramide path in human lung cell death,” American Journal of Respiratory Cell and Molecular Biology, vol. 22, no. 4, pp. 460–468, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. S. N. Lavrentiadou, C. Chan, T. Kawcak et al., “Ceramide-mediated apoptosis in lung epithelial cells is regulated by glutathione,” American Journal of Respiratory Cell and Molecular Biology, vol. 25, no. 6, pp. 676–684, 2001. View at Publisher · View at Google Scholar · View at Scopus
  28. S. Filosto, S. Castillo, A. Danielson et al., “Neutral sphingomyelinase 2: a novel target in cigarette smoke-induced apoptosis and lung injury,” American Journal of Respiratory Cell and Molecular Biology, vol. 44, no. 3, pp. 350–360, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. T. Goldkorn, T. Ravid, and E. M. Khan, “Life and death decisions: ceramide generation and EGF receptor trafficking are modulated by oxidative stress,” Antioxidants and Redox Signaling, vol. 7, no. 1-2, pp. 119–128, 2005. View at Publisher · View at Google Scholar · View at Scopus
  30. E. Abraham, “Neutrophils and acute lung injury,” Critical Care Medicine, vol. 31, pp. S195–S199, 2003. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Levy, S. S. Castillo, and T. Goldkorn, “nSMase2 activation and trafficking are modulated by oxidative stress to induce apoptosis,” Biochemical and Biophysical Research Communications, vol. 344, no. 3, pp. 900–905, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. S. S. Castillo, M. Levy, C. Wang, J. V. Thaikoottathil, E. Khan, and T. Goldkorn, “Nitric oxide-enhanced caspase-3 and acidic sphingomyelinase interaction: a novel mechanism by which airway epithelial cells escape ceramide-induced apoptosis,” Experimental Cell Research, vol. 313, no. 4, pp. 816–823, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. B. J. Pettus, C. E. Chalfant, and Y. A. Hannun, “Sphingolipids in inflammation: roles and implications,” Current Molecular Medicine, vol. 4, no. 4, pp. 405–418, 2004. View at Publisher · View at Google Scholar · View at Scopus
  34. S. S. Castillo, M. Levy, J. V. Thaikoottathil, and T. Goldkorn, “Reactive nitrogen and oxygen species activate different sphingomyelinases to induce apoptosis in airway epithelial cells,” Experimental Cell Research, vol. 313, no. 12, pp. 2680–2686, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. J. G. N. Garcia, F. Liu, A. D. Verin et al., “Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement,” The Journal of Clinical Investigation, vol. 108, no. 5, pp. 689–701, 2001. View at Publisher · View at Google Scholar · View at Scopus
  36. M. Maceyka and S. Spiegel, “Sphingolipid metabolites in inflammatory disease,” Nature, vol. 510, no. 7503, pp. 58–67, 2014. View at Publisher · View at Google Scholar · View at Scopus
  37. J. D. Saba and T. Hla, “Point-counterpoint of sphingosine 1-phosphate metabolism,” Circulation Research, vol. 94, no. 6, pp. 724–734, 2004. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Spiegel and S. Milstien, “Sphingosine-1-phosphate: an enigmatic signalling lipid,” Nature Reviews Molecular Cell Biology, vol. 4, no. 5, pp. 397–407, 2003. View at Publisher · View at Google Scholar · View at Scopus
  39. A. Abe, M. Hiraoka, S. Wild, S. E. Wilcoxen, R. Paine III, and J. A. Shayman, “Lysosomal phospholipase A2 is selectively expressed in alveolar macrophages,” The Journal of Biological Chemistry, vol. 279, no. 41, pp. 42605–42611, 2004. View at Publisher · View at Google Scholar · View at Scopus
  40. Y. Zhao, S. K. Kalari, P. V. Usatyuk et al., “Intracellular generation of sphingosine 1-phosphate in human lung endothelial cells: role of lipid phosphate phosphatase-1 and sphingosine kinase 1,” The Journal of Biological Chemistry, vol. 282, no. 19, pp. 14165–14177, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. T. Abbasi and J. G. N. Garcia, “Sphingolipids in lung endothelial biology and regulation of vascular integrity,” Handbook of Experimental Pharmacology, vol. 216, pp. 201–226, 2013. View at Publisher · View at Google Scholar · View at Scopus
  42. Y. Kasahara, R. M. Tuder, L. Taraseviciene-Stewart et al., “Inhibition of VEGF receptors causes lung cell apoptosis and emphysema,” The Journal of Clinical Investigation, vol. 106, no. 11, pp. 1311–1319, 2000. View at Publisher · View at Google Scholar · View at Scopus
  43. K. J. Diab, J. J. Adamowicz, K. Kamocki et al., “Stimulation of sphingosine 1-phosphate signaling as an alveolar cell survival strategy in emphysema,” American Journal of Respiratory and Critical Care Medicine, vol. 181, no. 4, pp. 344–352, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. I. Petrache, V. Natarajan, L. Zhen et al., “Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice,” Nature Medicine, vol. 11, no. 5, pp. 491–498, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. S. Mandala, R. Hajdu, J. Bergstrom et al., “Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists,” Science, vol. 296, no. 5566, pp. 346–349, 2002. View at Publisher · View at Google Scholar · View at Scopus
  46. L. Wang, S. Sammani, L. Moreno-Vinasco et al., “FTY720 (S)-phosphonate preserves sphingosine 1-phosphate receptor 1 expression and Exhibits superior barrier protection to FTY720 in acute lung injury,” Critical Care Medicine, vol. 42, no. 3, pp. e189–e199, 2014. View at Publisher · View at Google Scholar · View at Scopus
  47. L. O. Myat, S. Thangada, M.-T. Wu et al., “Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor,” The Journal of Biological Chemistry, vol. 282, no. 12, pp. 9082–9089, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. E. V. Berdyshev, I. Gorshkova, A. Skobeleva et al., “FTY720 inhibits ceramide synthases and up-regulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells,” The Journal of Biological Chemistry, vol. 284, no. 9, pp. 5467–5477, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. R. T. Dobrowsky, C. Kamibayashi, M. C. Mumby, and Y. A. Hannun, “Ceramide activates heterotrimeric protein phosphatase 2A,” Journal of Biological Chemistry, vol. 268, no. 21, pp. 15523–15530, 1993. View at Google Scholar · View at Scopus
  50. A. Mukhopadhyay, S. A. Saddoughi, P. Song et al., “Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling,” The FASEB Journal, vol. 23, no. 3, pp. 751–763, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. T. T. Cornell, V. Hinkovska-Galcheva, L. Sun et al., “Ceramide-dependent PP2A regulation of TNFα-induced IL-8 production in respiratory epithelial cells,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 296, no. 5, pp. L849–L856, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. K. Baudiß, C. K. Ayata, Z. Lazar et al., “Ceramide-1-phosphate inhibits cigarette smoke-induced airway inflammation,” The European Respiratory Journal, vol. 45, no. 6, pp. 1669–1680, 2015. View at Publisher · View at Google Scholar
  53. D. Avni, A. Philosoph, M. M. Meijler, and T. Zor, “The ceramide-1-phosphate analogue PCERA-1 modulates tumour necrosis factor-α and interleukin-10 production in macrophages via the cAMP–PKA–CREB pathway in a GTP-dependent manner,” Immunology, vol. 129, no. 3, pp. 375–385, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. S. Uhlig, R. Göggel, and S. Engel, “Mechanisms of platelet-activating factor (PAF)-mediated responses in the lung,” Pharmacological Reports, vol. 57, supplement, pp. 206–221, 2006. View at Google Scholar · View at Scopus
  55. W. M. Kuebler, Y. Yang, R. Samapati, and S. Uhlig, “Vascular barrier regulation by PAF, ceramide, caveolae, and NO—an intricate signaling network with discrepant effects in the pulmonary and systemic vasculature,” Cellular Physiology and Biochemistry, vol. 26, no. 1, pp. 29–40, 2010. View at Publisher · View at Google Scholar · View at Scopus
  56. J. Balsinde, M. A. Balboa, and E. A. Dennis, “Inflammatory activation of arachidonic acid signaling in murine P388D1 macrophages via sphingomyelin synthesis,” The Journal of Biological Chemistry, vol. 272, no. 33, pp. 20373–20377, 1997. View at Publisher · View at Google Scholar · View at Scopus
  57. R. Newton, L. Hart, K. F. Chung, and P. J. Barnes, “Ceramide induction of COX-2 and PGE2 in pulmonary A549 cells does not involve activation of NF-κB,” Biochemical and Biophysical Research Communications, vol. 277, no. 3, pp. 675–679, 2000. View at Publisher · View at Google Scholar · View at Scopus
  58. W. Stremmel, A. Hanemann, A. Braun et al., “Delayed release phosphatidylcholine as new therapeutic drug for ulcerative colitis—a review of three clinical trials,” Expert Opinion on Investigational Drugs, vol. 19, no. 12, pp. 1623–1630, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. E. Feige, I. Mendel, J. George, N. Yacov, and D. Harats, “Modified phospholipids as anti-inflammatory compounds,” Current Opinion in Lipidology, vol. 21, no. 6, pp. 525–529, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. J. Vivekananda, D. Smith, and R. J. King, “Sphingomyelin metabolites inhibit sphingomyelin synthase and CTP: phosphocholine cytidylyltransferase,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 281, no. 1, pp. L98–L107, 2001. View at Google Scholar · View at Scopus
  61. S. Awasthi, J. Vivekananda, V. Awasthi, D. Smith, and R. J. King, “CTP:Phosphocholine cytidylyltransferase inhibition by ceramide via PKC-α, p38 MAPK, cPLA2, and 5-lipoxygenase,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 281, no. 1, pp. L108–L118, 2001. View at Google Scholar · View at Scopus
  62. M. Murakami and I. Kudo, “New phospholipase A2 isozymes with a potential role in atherosclerosis,” Current Opinion in Lipidology, vol. 14, no. 5, pp. 431–436, 2003. View at Publisher · View at Google Scholar · View at Scopus
  63. Z. Xu, J. Zhou, D. M. McCoy, and R. K. Mallampalli, “LASS5 is the predominant ceramide synthase isoform involved in de novo sphingolipid synthesis in lung epithelia,” Journal of Lipid Research, vol. 46, no. 6, pp. 1229–1238, 2005. View at Publisher · View at Google Scholar · View at Scopus
  64. A. J. Ryan, D. M. McCoy, S. E. McGowan, R. G. Salome, and R. K. Mallampalli, “Alveolar sphingolipids generated in response to TNF-α modifies surfactant biophysical activity,” Journal of Applied Physiology, vol. 94, no. 1, pp. 253–258, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. P. Miklavc, O. H. Wittekindt, E. Felder, and P. Dietl, “Ca2+-dependent actin coating of lamellar bodies after exocytotic fusion: a prerequisite for content release or kiss-and-run,” Annals of the New York Academy of Sciences, vol. 1152, pp. 43–52, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. L. Sparkman, H. Chandru, and V. Boggaram, “Ceramide decreases surfactant protein B gene expression via downregulation of TTF-1 DNA binding activity,” American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 290, no. 2, pp. L351–L358, 2006. View at Publisher · View at Google Scholar · View at Scopus
  67. A. H. Merrill Jr., E. Wang, J. Stevens, and G. W. Brumley, “Activities of the initial enzymes of glycerolipid and sphingolipid synthesis in lung microsomes from rats exposed to air or 85% oxygen,” Biochemical and Biophysical Research Communications, vol. 119, no. 3, pp. 995–1000, 1984. View at Publisher · View at Google Scholar · View at Scopus
  68. N. Kolliputi, L. Galam, P. T. Parthasarathy, S. M. Tipparaju, and R. F. Lockey, “NALP-3 inflammasome silencing attenuates ceramide-induced transepithelial permeability,” Journal of Cellular Physiology, vol. 227, no. 9, pp. 3310–3316, 2012. View at Publisher · View at Google Scholar · View at Scopus
  69. J. Tibboel, S. Joza, I. Reiss, J. C. de Jongste, and M. Post, “Amelioration of hyperoxia-induced lung injury using a sphingolipid-based intervention,” The European Respiratory Journal, vol. 42, no. 3, pp. 776–784, 2013. View at Publisher · View at Google Scholar · View at Scopus
  70. S. Yu, M. Shi, C. Liu et al., “Time course changes of oxidative stress and inflammation in hyperoxia-induced acute lung injury in rats,” Iranian Journal of Basic Medical Sciences, vol. 18, no. 1, pp. 98–103, 2015. View at Google Scholar · View at Scopus
  71. H. Rauvala and M. Hallman, “Glycolipid accumulation in bronchoalveolar space in adult respiratory distress syndrome,” Journal of Lipid Research, vol. 25, no. 11, pp. 1257–1262, 1984. View at Google Scholar · View at Scopus
  72. W. Drobnik, G. Liebisch, F.-X. Audebert et al., “Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients,” Journal of Lipid Research, vol. 44, no. 4, pp. 754–761, 2003. View at Publisher · View at Google Scholar · View at Scopus
  73. R. Göggell, S. Winoto-Morbach, G. Vielhaber et al., “PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide,” Nature Medicine, vol. 10, no. 2, pp. 155–160, 2004. View at Publisher · View at Google Scholar · View at Scopus
  74. P. von Bismarck, C.-F. G. Wistädt, K. Klemm et al., “Improved pulmonary function by acid sphingomyelinase inhibition in a newborn piglet lavage model,” American Journal of Respiratory and Critical Care Medicine, vol. 177, no. 11, pp. 1233–1241, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. R. Dhami, X. He, and E. H. Schuchman, “Acid sphingomyelinase deficiency attenuates bleomycin-induced lung inflammation and fibrosis in mice,” Cellular Physiology and Biochemistry, vol. 26, no. 4-5, pp. 749–760, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. J. Chen, H. Tang, J. R. Sysol et al., “The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension,” American Journal of Respiratory and Critical Care Medicine, vol. 190, no. 9, pp. 1032–1043, 2014. View at Publisher · View at Google Scholar
  77. V. Natarajan, S. M. Dudek, J. R. Jacobson et al., “Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury,” American Journal of Respiratory Cell and Molecular Biology, vol. 49, no. 1, pp. 6–17, 2013. View at Publisher · View at Google Scholar · View at Scopus
  78. B. Mathew, J. R. Jacobson, E. Berdyshev et al., “Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs,” The FASEB Journal, vol. 25, no. 10, pp. 3388–3400, 2011. View at Publisher · View at Google Scholar · View at Scopus
  79. W.-C. Lin, C.-F. Lin, C.-L. Chen, C.-W. Chen, and Y.-S. Lin, “Inhibition of neutrophil apoptosis via sphingolipid signaling in acute lung injury,” The Journal of Pharmacology and Experimental Therapeutics, vol. 339, no. 1, pp. 45–53, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. S. Ren, C. Xin, J. Pfeilschifter, and A. Huwiler, “A novel mode of action of the putative sphingosine kinase inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SKI II): induction of lysosomal sphingosine kinase 1 degradation,” Cellular Physiology and Biochemistry, vol. 26, no. 1, pp. 97–104, 2010. View at Publisher · View at Google Scholar · View at Scopus
  81. W. P. R. Verdurmen, M. Thanos, I. R. Ruttekolk, E. Gulbins, and R. Brock, “Cationic cell-penetrating peptides induce ceramide formation via acid sphingomyelinase: implications for uptake,” Journal of Controlled Release, vol. 147, no. 2, pp. 171–179, 2010. View at Publisher · View at Google Scholar · View at Scopus
  82. A. Mehta, “Cystic fibrosis as a bowel cancer syndrome and the potential role of CK2,” Molecular and Cellular Biochemistry, vol. 316, no. 1-2, pp. 169–175, 2008. View at Publisher · View at Google Scholar · View at Scopus
  83. H. Hamai, F. Keyserman, L. M. Quittell, and T. S. Worgall, “Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling,” Journal of Lipid Research, vol. 50, no. 6, pp. 1101–1108, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. M. Bodas, T. Min, S. Mazur, and N. Vij, “Critical modifier role of membrane-cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysema,” Journal of Immunology, vol. 186, no. 1, pp. 602–613, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. F. R. Long, R. S. Williams, and R. G. Castile, “Structural airway abnormalities in infants and young children with cystic fibrosis,” The Journal of Pediatrics, vol. 144, no. 2, pp. 154–161, 2004. View at Publisher · View at Google Scholar · View at Scopus
  86. S. P. De Langhe, G. Carraro, D. Warburton, M. K. Hajihosseini, and S. Bellusci, “Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung,” Developmental Biology, vol. 299, no. 1, pp. 52–62, 2006. View at Publisher · View at Google Scholar · View at Scopus
  87. A. Ornoy, J. Arnon, D. Katznelson, M. Granat, B. Caspi, and J. Chemke, “Pathological confirmation of cystic fibrosis in the fetus following prenatal diagnosis,” American Journal of Medical Genetics, vol. 28, no. 4, pp. 935–947, 1987. View at Publisher · View at Google Scholar
  88. L. C. Boujaoude, C. Bradshaw-Wilder, C. Mao et al., “Cystic fibrosis transmembrane regulator regulates uptake of sphingoid base phosphates and lysophosphatidic acid: modulation of cellular activity of sphingosine 1-phosphate,” The Journal of Biological Chemistry, vol. 276, no. 38, pp. 35258–35264, 2001. View at Publisher · View at Google Scholar · View at Scopus
  89. S. A. McColley, V. Stellmach, S. R. Boas, M. Jain, and S. E. Crawford, “Serum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation,” American Journal of Respiratory and Critical Care Medicine, vol. 161, no. 6, pp. 1877–1880, 2000. View at Publisher · View at Google Scholar · View at Scopus
  90. M. B. Brown, W. R. Hunt, J. E. Noe et al., “Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke,” Pulmonary Circulation, vol. 4, no. 2, pp. 260–268, 2014. View at Publisher · View at Google Scholar
  91. V. Teichgräber, M. Ulrich, N. Endlich et al., “Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis,” Nature Medicine, vol. 14, no. 4, pp. 382–391, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. A. Caretti, A. Bragonzi, M. Facchini et al., “Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis,” Biochimica et Biophysica Acta: General Subjects, vol. 1840, no. 1, pp. 586–594, 2014. View at Publisher · View at Google Scholar · View at Scopus
  93. S. Sahu and W. S. Lynn, “Lipid composition of airway secretions from patients with asthma and patients with cystic fibrosis,” The American Review of Respiratory Disease, vol. 115, no. 2, pp. 233–239, 1977. View at Google Scholar · View at Scopus
  94. S. Sahu and W. S. Lynn, “Lipid composition of sputum from patients with asthma and patients with cystic fibrosis,” Inflammation, vol. 3, no. 1, pp. 27–36, 1978. View at Publisher · View at Google Scholar · View at Scopus
  95. M. Brodlie, M. C. McKean, G. E. Johnson et al., “Ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis lung disease,” American Journal of Respiratory and Critical Care Medicine, vol. 182, no. 3, pp. 369–375, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. M. Ulrich, D. Worlitzsch, S. Viglio et al., “Alveolar inflammation in cystic fibrosis,” Journal of Cystic Fibrosis, vol. 9, no. 3, pp. 217–227, 2010. View at Publisher · View at Google Scholar · View at Scopus
  97. K. A. Becker, B. Henry, R. Ziobro, B. Tümmler, E. Gulbins, and H. Grassmé, “Role of CD95 in pulmonary inflammation and infection in cystic fibrosis,” Journal of Molecular Medicine, vol. 90, no. 9, pp. 1011–1023, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. C. Guilbault, G. Wojewodka, Z. Saeed et al., “Cystic fibrosis fatty acid imbalance is linked to ceramide deficiency and corrected by fenretinide,” American Journal of Respiratory Cell and Molecular Biology, vol. 41, no. 1, pp. 100–106, 2009. View at Publisher · View at Google Scholar · View at Scopus
  99. M.-C. Morales, G. Pérez-Yarza, N. N. Rementería et al., “4-HPR-mediated leukemia cell cytotoxicity is triggered by ceramide-induced mitochondrial oxidative stress and is regulated downstream by Bcl-2,” Free Radical Research, vol. 41, no. 5, pp. 591–601, 2007. View at Publisher · View at Google Scholar · View at Scopus
  100. K. A. Becker, J. Riethmüller, A. Lüth, G. Döring, B. Kleuser, and E. Gulbins, “Acid sphingomyelinase inhibitors normalize pulmonary ceramide and inflammation in cystic fibrosis,” American Journal of Respiratory Cell and Molecular Biology, vol. 42, no. 6, pp. 716–724, 2010. View at Publisher · View at Google Scholar · View at Scopus
  101. L. Guillot, N. Nathan, O. Tabary et al., “Alveolar epithelial cells: master regulators of lung homeostasis,” International Journal of Biochemistry & Cell Biology, vol. 45, no. 11, pp. 2568–2573, 2013. View at Publisher · View at Google Scholar · View at Scopus
  102. V. Sender and C. Stamme, “Lung cell-specific modulation of LPS-induced TLR4 receptor and adaptor localization,” Communicative & Integrative Biology, vol. 7, no. 5, Article ID e29053, 2014. View at Publisher · View at Google Scholar · View at Scopus
  103. K. A. Becker, B. Tümmler, E. Gulbins, and H. Grassmé, “Accumulation of ceramide in the trachea and intestine of cystic fibrosis mice causes inflammation and cell death,” Biochemical and Biophysical Research Communications, vol. 403, no. 3-4, pp. 368–374, 2010. View at Publisher · View at Google Scholar · View at Scopus
  104. E. Barasch, Z. Vered, A. Shotan, D. Freimark, and B. Rabinowitz, “Dissecting aortic aneurysm—failure of standard noninvasive and invasive diagnostic techniques,” Cardiology, vol. 79, no. 4, pp. 309–313, 1991. View at Publisher · View at Google Scholar · View at Scopus
  105. A. Di, M. E. Brown, L. V. Deriy et al., “CFTR regulates phagosome acidification in macrophages and alters bactericidal activity,” Nature Cell Biology, vol. 8, no. 9, pp. 933–944, 2006. View at Publisher · View at Google Scholar · View at Scopus
  106. Y. Zhang, X. Li, H. Grassmé, G. Döring, and E. Gulbins, “Alterations in ceramide concentration and pH determine the release of reactive oxygen species by Cftr-deficient macrophages on infection,” The Journal of Immunology, vol. 184, no. 9, pp. 5104–5111, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. J. Noe, D. Petrusca, N. Rush et al., “CFTR regulation of intracellular pH and ceramides is required for lung endothelial cell apoptosis,” American Journal of Respiratory Cell and Molecular Biology, vol. 41, no. 3, pp. 314–323, 2009. View at Publisher · View at Google Scholar · View at Scopus
  108. Y. Pewzner-Jung, S. Tavakoli Tabazavareh, H. Grassmé et al., “Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa,” EMBO Molecular Medicine, vol. 6, no. 9, pp. 1205–1214, 2014. View at Publisher · View at Google Scholar · View at Scopus
  109. H. Barriere, M. Bagdany, F. Bossard et al., “Revisiting the role of cystic fibrosis transmembrane conductance regulator and counterion permeability in the pH regulation of endocytic organelles,” Molecular Biology of the Cell, vol. 20, no. 13, pp. 3125–3141, 2009. View at Publisher · View at Google Scholar · View at Scopus
  110. P. M. Haggie and A. S. Verkman, “Unimpaired lysosomal acidification in respiratory epithelial cells in cystic fibrosis,” The Journal of Biological Chemistry, vol. 284, no. 12, pp. 7681–7686, 2009. View at Publisher · View at Google Scholar · View at Scopus
  111. R. Ziobro, B. Henry, M. J. Edwards, A. B. Lentsch, and E. Gulbins, “Ceramide mediates lung fibrosis in cystic fibrosis,” Biochemical and Biophysical Research Communications, vol. 434, no. 4, pp. 705–709, 2013. View at Publisher · View at Google Scholar · View at Scopus
  112. D.-H. Kim, Y.-S. Lee, Y.-M. Lee, S. Oh, Y.-P. Yun, and H.-S. Yoo, “Elevation of sphingoid base 1-phosphate as a potential contributor to hepatotoxicity in fumonisin B1-exposed mice,” Archives of Pharmacal Research, vol. 30, no. 8, pp. 962–969, 2007. View at Publisher · View at Google Scholar · View at Scopus
  113. N. Sharma, Q. He, and R. P. Sharma, “Sphingosine kinase activity confers resistance to apoptosis by fumonisin B1 in human embryonic kidney (HEK-293) cells,” Chemico-Biological Interactions, vol. 151, no. 1, pp. 33–42, 2004. View at Publisher · View at Google Scholar · View at Scopus
  114. A. Rab, S. M. Rowe, S. V. Raju, Z. Bebok, S. Matalon, and J. F. Collawn, “Cigarette smoke and CFTR: implications in the pathogenesis of COPD,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 305, no. 8, pp. L530–L541, 2013. View at Publisher · View at Google Scholar · View at Scopus
  115. H. Grassmé, A. Carpinteiro, M. J. Edwards, E. Gulbins, and K. A. Becker, “Regulation of the inflammasome by ceramide in cystic fibrosis lungs,” Cellular Physiology and Biochemistry, vol. 34, no. 1, pp. 45–55, 2014. View at Publisher · View at Google Scholar · View at Scopus
  116. J. Riethmüller, J. Anthonysamy, E. Serra, M. Schwab, G. Döring, and E. Gulbins, “Therapeutic efficacy and safety of amitriptyline in patients with cystic fibrosis,” Cellular Physiology and Biochemistry, vol. 24, no. 1-2, pp. 65–72, 2009. View at Publisher · View at Google Scholar · View at Scopus
  117. L. Nährlich, J. G. Mainz, C. Adams et al., “Therapy of CF-patients with amitriptyline and placebo—a randomised, double-blind, placebo-controlled phase IIb multicenter, cohort-study,” Cellular Physiology and Biochemistry, vol. 31, no. 4-5, pp. 505–512, 2013. View at Publisher · View at Google Scholar · View at Scopus
  118. Y. Itokazu, R. E. Pagano, A. S. Schroeder, S. M. O'Grady, A. H. Limper, and D. L. Marks, “Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased β1-integrin signaling and delayed wound repair,” American Journal of Physiology: Cell Physiology, vol. 306, no. 9, pp. C819–C830, 2014. View at Publisher · View at Google Scholar · View at Scopus
  119. S. Wang, P. Robinet, J. D. Smith, and K. Gulshan, “Free-cholesterol-mediated autophagy of ORMDL1 stimulates sphingomyelin biosynthesis,” Autophagy, vol. 11, no. 7, pp. 1207–1208, 2015. View at Publisher · View at Google Scholar
  120. N. M. White, D. Jiang, J. D. Burgess, I. R. Bederman, S. F. Previs, and T. J. Kelley, “Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 292, no. 2, pp. L476–L486, 2007. View at Publisher · View at Google Scholar · View at Scopus
  121. D. M. Mannino, D. M. Homa, L. J. Akinbami, E. S. Ford, and S. C. Redd, “Chronic obstructive pulmonary disease surveillance—United States, 1971–2000,” Morbidity and Mortality Weekly Report. Surveillance Summaries, vol. 51, no. 6, pp. 1–16, 2002. View at Google Scholar · View at Scopus
  122. A. S. Gershon, L. Warner, P. Cascagnette, J. C. Victor, and T. To, “Lifetime risk of developing chronic obstructive pulmonary disease: a longitudinal population study,” The Lancet, vol. 378, no. 9795, pp. 991–996, 2011. View at Publisher · View at Google Scholar · View at Scopus
  123. S. S. Salvi and P. J. Barnes, “Chronic obstructive pulmonary disease in non-smokers,” The Lancet, vol. 374, no. 9691, pp. 733–743, 2009. View at Publisher · View at Google Scholar · View at Scopus
  124. J. E. McDonough, R. Yuan, M. Suzuki et al., “Small-airway obstruction and emphysema in chronic obstructive pulmonary disease,” The New England Journal of Medicine, vol. 365, no. 17, pp. 1567–1575, 2011. View at Publisher · View at Google Scholar · View at Scopus
  125. Y. S. Prakash, “Airway smooth muscle in airway reactivity and remodeling: what have we learned?” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 305, no. 12, pp. L912–L933, 2013. View at Publisher · View at Google Scholar · View at Scopus
  126. C. R. Laratta and S. van Eeden, “Acute exacerbation of chronic obstructive pulmonary disease: cardiovascular links,” BioMed Research International, vol. 2014, Article ID 528789, 18 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  127. R. Aldonyte, E. Bagdonas, J. Raudoniute, and I. Bruzauskaite, “Novel aspects of pathogenesis and regeneration mechanisms in COPD,” International Journal of Chronic Obstructive Pulmonary Disease, vol. 10, no. 1, pp. 995–1013, 2015. View at Publisher · View at Google Scholar
  128. C. Martin, J. Frija-Masson, and P.-R. Burgel, “Targeting mucus hypersecretion: new therapeutic opportunities for COPD?” Drugs, vol. 74, no. 10, pp. 1073–1089, 2014. View at Publisher · View at Google Scholar · View at Scopus
  129. T. A. Packard, Q. Z. Li, G. P. Cosgrove, R. P. Bowler, and J. C. Cambier, “COPD is associated with production of autoantibodies to a broad spectrum of self-antigens, correlative with disease phenotype,” Immunologic Research, vol. 55, no. 1–3, pp. 48–57, 2013. View at Publisher · View at Google Scholar · View at Scopus
  130. S. Fujii, H. Hara, J. Araya et al., “Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease,” OncoImmunology, vol. 1, no. 5, pp. 630–641, 2012. View at Publisher · View at Google Scholar · View at Scopus
  131. S. W. Ryter, S.-J. Lee, and A. M. K. Choi, “Autophagy in cigarette smoke-induced chronic obstructive pulmonary disease,” Expert Review of Respiratory Medicine, vol. 4, no. 5, pp. 573–584, 2010. View at Publisher · View at Google Scholar · View at Scopus
  132. I. Petrache, T. R. Medler, A. T. Richter et al., “Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 295, no. 1, pp. L44–L53, 2008. View at Publisher · View at Google Scholar · View at Scopus
  133. M. Levy, E. Khan, M. Careaga, and T. Goldkorn, “Neutral sphingomyelinase 2 is activated by cigarette smoke to augment ceramide-induced apoptosis in lung cell death,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 297, no. 1, pp. L125–L133, 2009. View at Publisher · View at Google Scholar · View at Scopus
  134. T. Goldkorn, S. Filosto, and S. Chung, “Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor,” Antioxidants & Redox Signaling, vol. 21, no. 15, pp. 2149–2174, 2014. View at Publisher · View at Google Scholar
  135. S. Chung, S. Vu, S. Filosto, and T. Goldkorn, “Src regulates cigarette smoke-induced ceramide generation via neutral sphingomyelinase 2 in the airway epithelium,” American Journal of Respiratory Cell and Molecular Biology, vol. 52, no. 6, pp. 738–748, 2015. View at Publisher · View at Google Scholar
  136. S. Sammani, L. Moreno-Vinasco, T. Mirzapoiazova et al., “Differential effects of sphingosine 1-phosphate receptors on airway and vascular barrier function in the murine lung,” American Journal of Respiratory Cell and Molecular Biology, vol. 43, no. 4, pp. 394–402, 2010. View at Publisher · View at Google Scholar · View at Scopus
  137. Y. Gon, M. R. Wood, W. B. Kiosses et al., “S1P3 receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 26, pp. 9270–9275, 2005. View at Google Scholar
  138. F. Cordts, S. Pitson, C. Tabeling et al., “Expression profile of the sphingosine kinase signalling system in the lung of patients with chronic obstructive pulmonary disease,” Life Sciences, vol. 89, no. 21-22, pp. 806–811, 2011. View at Publisher · View at Google Scholar · View at Scopus
  139. E.-J. D. Oudijk, J.-W. J. Lammers, and L. Koenderman, “Systemic inflammation in chronic obstructive pulmonary disease,” The European Respiratory Journal. Supplement, vol. 22, no. 46, pp. 5s–13s, 2003. View at Google Scholar · View at Scopus
  140. R. Aldonyte, S. Eriksson, E. Piitulainen, A. Wallmark, and S. Janciauskiene, “Analysis of systemic biomarkers in COPD patients,” COPD: Journal of Chronic Obstructive Pulmonary Disease, vol. 1, no. 2, pp. 155–164, 2004. View at Publisher · View at Google Scholar · View at Scopus
  141. T. R. Martin, G. Raghu, R. J. Maunder, and S. C. Springmeyer, “The effects of chronic bronchitis and chronic air-flow obstruction on lung cell populations recovered by bronchoalveolar lavage,” The American Review of Respiratory Disease, vol. 132, no. 2, pp. 254–260, 1985. View at Google Scholar · View at Scopus
  142. A. K. Ravi, S. Khurana, J. Lemon et al., “Increased levels of soluble interleukin-6 receptor and CCL3 in COPD sputum,” Respiratory Research, vol. 15, article 103, 2014. View at Publisher · View at Google Scholar · View at Scopus
  143. T. M. Bahr, G. J. Hughes, M. Armstrong et al., “Peripheral blood mononuclear cell gene expression in chronic obstructive pulmonary disease,” American Journal of Respiratory Cell and Molecular Biology, vol. 49, no. 2, pp. 316–323, 2013. View at Publisher · View at Google Scholar · View at Scopus
  144. E. D. Telenga, R. F. Hoffmann, Ruben t'Kindt et al., “Untargeted lipidomic analysis in chronic obstructive pulmonary disease. Uncovering sphingolipids,” American Journal of Respiratory and Critical Care Medicine, vol. 190, no. 2, pp. 155–164, 2014. View at Publisher · View at Google Scholar · View at Scopus
  145. M. Tani, Y. Igarashi, and M. Ito, “Involvement of neutral ceramidase in ceramide metabolism at the plasma membrane and in extracellular milieu,” The Journal of Biological Chemistry, vol. 280, no. 44, pp. 36592–36600, 2005. View at Publisher · View at Google Scholar · View at Scopus
  146. R. P. Bowler, S. Jacobson, C. Cruickshank et al., “Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes,” American Journal of Respiratory and Critical Care Medicine, vol. 191, no. 3, pp. 275–284, 2015. View at Publisher · View at Google Scholar · View at Scopus
  147. J. D. Brain, “Macrophage damage in relation to the pathogenesis of lung diseases,” Environmental Health Perspectives, vol. 35, pp. 21–28, 1980. View at Publisher · View at Google Scholar · View at Scopus
  148. P. Kirkham, “Oxidative stress and macrophage function: a failure to resolve the inflammatory response,” Biochemical Society Transactions, vol. 35, no. 2, pp. 284–287, 2007. View at Publisher · View at Google Scholar · View at Scopus
  149. D. N. Petrusca, Y. Gu, J. J. Adamowicz et al., “Sphingolipid-mediated inhibition of apoptotic cell clearance by alveolar macrophages,” The Journal of Biological Chemistry, vol. 285, no. 51, pp. 40322–40332, 2010. View at Publisher · View at Google Scholar · View at Scopus
  150. D. Zabini, S. Crnkovic, H. Xu et al., “High-mobility group box-1 induces vascular remodelling processes via c-Jun activation,” Journal of Cellular and Molecular Medicine, vol. 19, no. 5, pp. 1151–1161, 2015. View at Publisher · View at Google Scholar
  151. E. Stacher, B. B. Graham, J. M. Hunt et al., “Modern age pathology of pulmonary arterial hypertension,” American Journal of Respiratory and Critical Care Medicine, vol. 186, no. 3, pp. 261–272, 2012. View at Publisher · View at Google Scholar · View at Scopus
  152. M. Bodas, T. Min, and N. Vij, “Lactosylceramide-accumulation in lipid-rafts mediate aberrant-autophagy, inflammation and apoptosis in cigarette smoke induced emphysema,” Apoptosis, vol. 20, pp. 725–739, 2015. View at Publisher · View at Google Scholar · View at Scopus