Review Article | Published:

Heparin-binding epidermal growth factor (HB-EGF) drives EMT in patients with COPD: implications for disease pathogenesis and novel therapies

Laboratory Investigationvolume 99pages150157 (2019) | Download Citation


Chronic obstructive pulmonary disease (COPD) is a progressive and devastating chronic lung condition that has a significant global burden, both medically and financially. Currently there are no medications that can alter the course of disease. At best, the drugs in clinical practice provide symptomatic relief to suffering patients by alleviating acute exacerbations. Most of current clinical research activities are in late severe disease with lesser attention given to early disease manifestations. There is as yet, a lack of understanding of the underlying mechanisms of disease progression and the molecular switches that are involved in their manifestation. Small airway fibrosis and obliteration are known to cause fixed airflow obstruction in COPD, and the consequential damage to the lung has an early onset. So far, there is little evidence of the mechanisms that underlie this aspect of pathology. However, emerging research confirms that airway epithelial reprogramming or epithelial to mesenchymal transition (EMT) is a key mechanism that drives fibrotic remodelling changes in smokers and patients with COPD. A recent study by Lai et al. further highlights the importance of EMT in smoking-related COPD pathology. The authors identify HB-EGF, an EGFR ligand, as a key driver of EMT and a potential new therapeutic target for the amelioration of EMT and airway remodelling. There are also wider implications in lung cancer prophylaxis, which is another major comorbidity associated with COPD. We consider that improved molecular understanding of the intricate pathways associated with epithelial cell plasticity in smokers and patients with COPD will have major therapeutic implications.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Eapen MS, Myers S, Walters EH, Sohal SS. Airway inflammation in chronic obstructive pulmonary disease (COPD): a true paradox. Expert Rev Respir Med. 2017;11:827–39.

  2. 2.

    Eapen MS, Sohal SS. Understanding novel mechanisms of microbial pathogenesis in chronic lung disease: implications for new therapeutic targets. Clin Sci. 2018;132:375–9.

  3. 3.

    Sohal SS. Inhaled corticosteroids and increased microbial load in COPD: potential role of epithelial adhesion molecules. Eur Respir J 2018;51.

  4. 4.

    Sohal SS, Eapen MS, Ward C, Walters EH. Airway inflammation and inhaled corticosteroids in COPD. Eur Respir J 2017;49.

  5. 5.

    Keely S, Talley NJ, Hansbro PM. Pulmonary-intestinal cross-talk in mucosal inflammatory disease. Mucosal Immunol. 2012;5:7–18.

  6. 6.

    Budden KF, Gellatly SL, Wood DL, et al. Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol. 2017;15:55–63.

  7. 7.

    World Health Organisation (WHO). Chronic obstructive pulmonary disease (COPD)-key facts. http://wwwwhoint/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd); 2016.

  8. 8.

    Lelieveld J, Evans JS, Fnais M, Giannadaki D, Pozzer A. The contribution of outdoor air pollution sources to premature mortality on a global scale. Nature. 2015;525:367.

  9. 9.

    Sohal S, Ward C, Danial W, Wood-Baker R, Walters EH. Recent advances in understanding inflammation and remodeling in the airways in chronic obstructive pulmonary disease. Expert Rev Respir Med. 2013;7:275–88.

  10. 10.

    Eapen MS, Myers S, Walters EH, Sohal SS. Airway inflammation in chronic obstructive pulmonary disease (COPD): a true paradox. Expert Rev Respir Med. 2017;11:827–39.

  11. 11.

    Jolly MK, Ward C, Eapen MS, et al. Epithelial-mesenchymal transition, a spectrum of states: role in lung development, homeostasis, and disease. Dev Dyn 2017;247:346-358.

  12. 12.

    Reid AT, Veerati PC, Gosens R, et al. Persistent induction of goblet cell differentiation in the airways: therapeutic approaches. Pharmacol Ther. 2018;185:155–69.

  13. 13.

    Brune K, Frank J, Schwingshackl A, Finigan J, Sidhaye VK. Pulmonary epithelial barrier function: some new players and mechanisms. Am J Physiol Lung Cell Mol Physiol. 2015;308:L731–L45.

  14. 14.

    Puchelle E, Zahm JM, Tournier JM, Coraux C. Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006;3:726–33.

  15. 15.

    Hallstrand TS, Hackett TL, Altemeier WA, et al. Airway epithelial regulation of pulmonary immune homeostasis and inflammation. Clin Immunol. 2014;151:1–15.

  16. 16.

    Eapen MS, Hansbro PM, McAlinden K, et al. Abnormal M1/M2 macrophage phenotype profiles in the small airway wall and lumen in smokers and chronic obstructive pulmonary disease (COPD). Sci Rep. 2017;7:13392.

  17. 17.

    Eapen MS, McAlinden K, Tan D, et al. Profiling cellular and inflammatory changes in the airway wall of mild to moderate COPD. Respirology. 2017;22:1125–32.

  18. 18.

    Peters EJ, Morice R, Benner SE, et al. Squamous metaplasia of the bronchial mucosa and its relationship to smoking. Chest. 1993;103:1429–32.

  19. 19.

    Crystal RG. Airway basal cells. The “smoking gun” of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;190:1355–62.

  20. 20.

    Eapen MS, Myers S, Lu W, et al. sE-cadherin and sVE-cadherin indicate active epithelial/endothelial to mesenchymal transition (EMT and EndoMT) in smokers and COPD: implications for new biomarkers and therapeutics. Biomarkers 2018;23:709-711.

  21. 21.

    Sohal SS. Airway basal cell reprogramming and EMT: potential key to understanding early COPD. Am J Respir Crit Care Med 2018;197:1644-1645.

  22. 22.

    Sohal SS. Epithelial and endothelial cell plasticity in chronic obstructive pulmonary disease (COPD). Respir Investig. 2017;55:104–13.

  23. 23.

    Sohal SS, Walters EH. Epithelial mesenchymal transition (EMT) in small airways of COPD patients. Thorax. 2013;68:783–4.

  24. 24.

    Sohal SS. Chronic obstructive pulmonary disease (COPD) and lung cancer: epithelial mesenchymal transition (EMT), the missing link? EBioMedicine. 2015;2:1578–9.

  25. 25.

    Kumar JM, Chris W, Suji EM, et al. Epithelial–mesenchymal transition, a spectrum of states: role in lung development, homeostasis, and disease. Dev Dyn. 2018;247:346–58.

  26. 26.

    Königshoff M. Lung cancer in pulmonary fibrosis: tales of epithelial cell plasticity. Respiration. 2011;81:353–8.

  27. 27.

    Sohal SS, Walters EH. Advanced non-small-cell lung cancer. N Engl J Med. 2017;377:1998–9.

  28. 28.

    Nowrin K, Sohal SS, Peterson G, Patel R, Walters EH. Epithelial-mesenchymal transition as a fundamental underlying pathogenic process in COPD airways: fibrosis, remodeling and cancer. Expert Rev Respir Med. 2014;8:547–59.

  29. 29.

    Mahmood MQ, Sohal SS, Shukla SD, et al. Epithelial mesenchymal transition in smokers: large versus small airways and relation to airflow obstruction. Int J Chron Obstruct Pulmon Dis. 2015;10:1515–24.

  30. 30.

    Schneider M, Hansen JL, Sheikh SP. S100A4: a common mediator of epithelial-mesenchymal transition, fibrosis and regeneration in diseases? J Mol Med. 2008;86:507–22.

  31. 31.

    Sohal S, Reid D, Soltani A, et al. Reticular basement membrane fragmentation and potential epithelial mesenchymal transition is exaggerated in the airways of smokers with chronic obstructive pulmonary disease. Respirology. 2010;15:930–8.

  32. 32.

    Soltani A, Reid DW, Sohal SS, et al. Basement membrane and vascular remodelling in smokers and chronic obstructive pulmonary disease: a cross-sectional study. Respir Res. 2010;11:105.

  33. 33.

    Sohal SS, Reid D, Soltani A, et al. Evaluation of epithelial mesenchymal transition in patients with chronic obstructive pulmonary disease. Respir Res. 2011;12:130.

  34. 34.

    Wang Q, Wang Y, Zhang Y, Zhang Y, Xiao W. The role of uPAR in epithelial-mesenchymal transition in small airway epithelium of patients with chronic obstructive pulmonary disease. Respir Res. 2013;14:67.

  35. 35.

    Ng Kee Kwong F, Nicholson AG, Harrison CL, et al. Is mitochondrial dysfunction a driving mechanism linking COPD to nonsmall cell lung carcinoma? Eur Respir Rev 2017;26.

  36. 36.

    Milara J, Peiró T, Serrano A, Cortijo J. Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax. 2013;68:410–20.

  37. 37.

    Milara J, Peiro T, Serrano A, et al. Roflumilast N-oxide inhibits bronchial epithelial to mesenchymal transition induced by cigarette smoke in smokers with COPD. Pulm Pharmacol Ther. 2014;28:138–48.

  38. 38.

    Gohy ST, Hupin C, Fregimilicka C, et al. Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition. Eur Respir J. 2015;45:1258–72.

  39. 39.

    Sohal SS, Eapen MS, Ward C, Walters EH. Epithelial Mesenchymal Transition (EMT): a necessary new therapeutic target in COPD? Am J Respir Crit Care Med 2017;196:393-394.

  40. 40.

    Sohal SS, Hansbro PM, Walters EH. Epithelial mesenchymal transition in chronic obstructive pulmonary disease, a precursor for epithelial cancers: understanding and translation to early therapy. Ann Am Thorac Soc. 2017;14:1491–2.

  41. 41.

    Sohal SS, Walters EH. Essential need for rethink of COPD airway pathology: implications for new drug approaches for prevention of lung cancer as well as small airway fibrosis. Int J Chron Obstruct Pulmon Dis. 2017;12:2677–9.

  42. 42.

    Soltani A, Walters EH, Reid DW, et al. Inhaled corticosteroid normalizes some but not all airway vascular remodeling in COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:2359–67.

  43. 43.

    Sohal SS. Endothelial to mesenchymal transition (EndMT): an active process in chronic obstructive pulmonary disease (COPD)? Respir Res. 2016;17:20.

  44. 44.

    Parimon T, Chien J, Bryson C, et al. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175:712–9.

  45. 45.

    Sohal SS. Fluticasone propionate and increased risk of pneumonia in COPD: is it PAFR-dependent? Int J Chron Obstruct Pulmon Dis. 2017;12:3425–7.

  46. 46.

    Eapen MS, Sharma P, Moodley YP, Hansbro PM, Sohal SS. Dysfunctional Immunity and Microbial Adhesion Molecules in Smoking-Induced Pneumonia. Am J Respir Crit Care Med. 2018 Oct 5. [Epub ahead of print].

  47. 47.

    Shukla SD, Sohal SS, Mahmood MQ, et al. Airway epithelial platelet-activating factor receptor expression is markedly upregulated in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2014;9:853–61.

  48. 48.

    Eapen MS, Hansbro PM, Larsson-Callerfelt AK, Jolly MK, Myers S, Sharma P, Jones B, Rahman MA, Markos J, Chia C, Larby J, Haug G, Hardikar A, Weber HC, Mabeza G, Cavalheri V, Khor YH, McDonald CF, Sohal SS. Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities. Drugs. 2018 Nov 3. [Epub ahead of print].

  49. 49.

    Liu T-C, Jin X, Wang Y, Wang K. Role of epidermal growth factor receptor in lung cancer and targeted therapies. Am J Cancer Res. 2017;7:187–202.

  50. 50.

    Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010;2:48–51.

  51. 51.

    Shaykhiev R, Crystal RG. Early events in the pathogenesis of chronic obstructive pulmonary disease. smoking-induced reprogramming of airway epithelial basal progenitor cells. Ann Am Thorac Soc. 2014;11:S252–S8.

  52. 52.

    Shaykhiev R, Zuo W-L, Chao I, et al. EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype. Proc Natl Acad Sci USA. 2013;110:12102–7.

  53. 53.

    Kedzierski L, Tate MD, Hsu AC, et al. Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling. Elife 2017;6.

  54. 54.

    Minor DM, Proud D. Role of human rhinovirus in triggering human airway epithelial-mesenchymal transition. Respir Res. 2017;18:110.

  55. 55.

    Mahmood MQ, Ward C, Muller HK, Sohal SS, Walters EH. Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease. Med Oncol. 2017;34:45.

  56. 56.

    Shigeki H, Hidehiko I, Chie M, et al. Membrane‐anchored growth factors, the epidermal growth factor family: Beyond receptor ligands. Cancer Sci. 2008;99:214–20.

  57. 57.

    Schneider Marlon R, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol. 2008;218:460–6.

  58. 58.

    Li L, Qi L, Liang Z, et al. Transforming growth factor-β1 induces EMT by the transactivation of epidermal growth factor signaling through HA/CD44 in lung and breast cancer cells. Int J Mol Med. 2015;36:113–22.

  59. 59.

    Daub H, Ulrich Weiss F, Wallasch C, Ullrich A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature. 1996;379:557.

  60. 60.

    Uchiyama-Tanaka Y, Matsubara H, Mori Y, et al. Involvement of HB-EGF and EGF receptor <em>trans</em>activation in TGF-β–mediated fibronectin expression in mesangial cells. Kidney Int. 2002;62:799–808.

  61. 61.

    Lo H-W, Hsu S-C, Xia W, et al. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of <em>TWIST</em> gene expression. Cancer Res. 2007;67:9066–76.

  62. 62.

    Stoll SW, Rittié L, Johnson JL, Elder JT. Heparin-binding EGF-like growth factor promotes epithelial-mesenchymal transition in human keratinocytes. J Invest Dermatol. 2012;132:2148–57.

  63. 63.

    Lai T, Li Y, Chen M, et al. Heparin-binding epidermal growth factor contributes to COPD disease severity by modulating airway fibrosis and pulmonary epithelial–mesenchymal transition. Lab Investig. 2018;98:1159–69.

  64. 64.

    Mahmood MQ, Reid D, Ward C, et al. Transforming growth factor (TGF) beta1 and Smad signalling pathways: a likely key to EMT-associated COPD pathogenesis. Respirology. 2017;22:133–40.

  65. 65.

    Springer J, Scholz FR, Peiser C, Groneberg DA, Fischer A. SMAD-signaling in chronic obstructive pulmonary disease: transcriptional down-regulation of inhibitory SMAD 6 and 7 by cigarette smoke. Biol Chem. 2004;385:649–53.

  66. 66.

    Uttamsingh S, Bao X, Nguyen KT, et al. Synergistic effect between EGF and TGF-beta1 in inducing oncogenic properties of intestinal epithelial cells. Oncogene. 2008;27:2626–34.

  67. 67.

    Baarsma HA, Königshoff M. ‘WNT-er is coming’: WNT signalling in chronic lung diseases. Thorax. 2017;72:746–59.

  68. 68.

    Zou W, Zou Y, Zhao Z, Li B, Ran P. Nicotine-induced epithelial-mesenchymal transition via Wnt/beta-catenin signaling in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2013;304:L199–209.

  69. 69.

    Baarsma HA, Spanjer AIR, Haitsma G, et al. Activation of WNT/β-catenin signaling in pulmonary fibroblasts by TGF-β1 is increased in chronic obstructive pulmonary disease. PLoS One. 2011;6:e25450.

  70. 70.

    DiRenzo DM, Chaudhary MA, Shi X, et al. A crosstalk between TGF-β/Smad3 and Wnt/β-catenin pathways promotes vascular smooth muscle cell proliferation. Cell Signal. 2016;28:498–505.

  71. 71.

    Mahmood MQ, Walters EH, Shukla SD, et al. β-catenin, Twist and Snail: transcriptional regulation of EMT in smokers and COPD, and relation to airflow obstruction. Sci Rep. 2017;7:10832.

  72. 72.

    Talele Nilesh P, Fradette J, Davies John E, Kapus A, Hinz B. Expression of α-smooth muscle actin determines the fate of mesenchymal stromal cells. Stem Cell Rep. 2015;4:1016–30.

  73. 73.

    Löfdahl M, Kaarteenaho R, Lappi-Blanco E, Tornling G, Sköld MC. Tenascin-C and alpha-smooth muscle actin positive cells are increased in the large airways in patients with COPD. Respir Res. 2011;12:48.

  74. 74.

    Karvonen HM, Lehtonen ST, Harju T, et al. Myofibroblast expression in airways and alveoli is affected by smoking and COPD. Respir Res. 2013;14:84.

  75. 75.

    Hallgren O, Rolandsson S, Andersson-Sjöland A, et al. Enhanced ROCK1 dependent contractility in fibroblast from chronic obstructive pulmonary disease patients. J Transl Med. 2012;10:171.

  76. 76.

    Hallgren O, Nihlberg K, Dahlbäck M, et al. Altered fibroblast proteoglycan production in COPD. Respir Res. 2010;11:55.

  77. 77.

    Larsson-Callerfelt A-K, Hallgren O, Andersson-Sjöland A, et al. Defective alterations in the collagen network to prostacyclin in COPD lung fibroblasts. Respir Res. 2013;14:21.

  78. 78.

    Harju T, Kinnula VL, Pääkkö P, et al. Variability in the precursor proteins of collagen I and III in different stages of COPD. Respir Res. 2010;11:165.

  79. 79.

    Liu G, Cooley MA, Jarnicki AG, et al. Fibulin-1 regulates the pathogenesis of tissue remodeling in respiratory diseases. JCI Insight 2016;1.

  80. 80.

    Hsu AC, Starkey MR, Hanish I, et al. Targeting PI3K-p110alpha suppresses influenza virus infection in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191:1012–23.

  81. 81.

    Starkey MR, Jarnicki AG, Essilfie AT, et al. Murine models of infectious exacerbations of airway inflammation. Curr Opin Pharmacol. 2013;13:337–44.

  82. 82.

    Shukla SD, Fairbairn RL, Gell DA, et al. An antagonist of the platelet-activating factor receptor inhibits adherence of both nontypeable Haemophilus influenzae and Streptococcus pneumoniae to cultured human bronchial epithelial cells exposed to cigarette smoke. Int J Chron Obstruct Pulmon Dis. 2016;11:1647–55.

  83. 83.

    Shukla SD, Mahmood MQ, Weston S, et al. The main rhinovirus respiratory tract adhesion site (ICAM-1) is upregulated in smokers and patients with chronic airflow limitation (CAL). Respir Res. 2017;18:6.

  84. 84.

    Shukla SD, Muller HK, Latham R, Sohal SS, Walters EH. Platelet-activating factor receptor (PAFr) is upregulated in small airways and alveoli of smokers and COPD patients. Respirology. 2016;21:504–10.

  85. 85.

    Shukla SD, Sohal SS, O'Toole RF, Eapen MS, Walters EH. Platelet activating factor receptor: gateway for bacterial chronic airway infection in chronic obstructive pulmonary disease and potential therapeutic target. Expert Rev Respir Med. 2015;9:473–85.

  86. 86.

    Sohal SS, Eapen MS, Shukla SD, et al. Novel insights into chronic obstructive pulmonary disease (COPD): an overview. Eur Med J—Respir. 2014;2:81–7.

  87. 87.

    Sohal SS, Hansbro PM, Shukla SD, Eapen MS, Walters EH. Potential mechanisms of microbial pathogens in idiopathic interstitial lung disease. Chest. 2017;152:899–900.

  88. 88.

    Jones B, Donovan C, Liu G, et al. Animal models of COPD: what do they tell us? Respirology. 2017;22:21–32.

  89. 89.

    Sohal SS, Mahmood QM, Walters HE. Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer. Clin Transl Med. 2014;3:33.

  90. 90.

    Sohal SS, Reid D, Soltani A, et al. Changes in airway histone deacetylase2 in smokers and COPD with inhaled corticosteroids: a randomized controlled trial. PLoS One. 2013;8:e64833.

  91. 91.

    Sohal SS, Soltani A, Reid D, et al. A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial-mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study. Int J Chron Obstruct Pulmon Dis. 2014;9:533–42.

  92. 92.

    Soltani A, Sohal SS, Reid D, et al. Vessel-associated transforming growth factor-beta1 (TGF-&946 1) is increased in the bronchial reticular basement membrane in COPD and normal smokers. PLoS One. 2012;7:1–5.

  93. 93.

    Simpson JL, Powell H, Baines KJ, et al. The effect of azithromycin in adults with stable neutrophilic COPD: a double blind randomised, placebo controlled trial. PLoS One. 2014;9:e105609.

  94. 94.

    Eapen MS, Kota A, Vindin H. et al. Apoptosis signal-regulating kinase 1 (ASK1) inhibition attenuates human airway smooth muscle growth and migration in chronic obstructive pulmonary disease (COPD). Clin Sci . 2018;132:1615–27.

  95. 95.

    Jaffar J, Unger S, Corte TJ, et al. Fibulin-1 predicts disease progression in patients with idiopathic pulmonary fibrosis. Chest. 2014;146:1055–63.

Download references


SSS is supported by Clifford Craig Foundation Launceston and Thoracic Society of Australia and New Zealand (TSANZ) and Boehringer Ingelheim COPD Research Award, PS is supported by Rebecca L. Cooper Medical Research Foundation, Australia and Chancellors Fellowship Programme, University of Technology Sydney (UTS). PMH is supported by an NHMRC Principal Research Fellowship and a Brawn Fellowship, Faculty of Health, University of Newcastle.

Author information


  1. Respiratory Translational Research Group, Department of Laboratory Medicine, College of Health and Medicine, University of Tasmania, Launceston, TAS, 7248, Australia

    • Mathew Suji Eapen
    • , Isobel E. Thompson
    • , Wenying Lu
    • , Stephen Myers
    •  & Sukhwinder Singh Sohal
  2. Medical Sciences, University of Technology Sydney, Sydney, NSW, 2007, Australia

    • Pawan Sharma
  3. Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, 2037, Australia

    • Pawan Sharma
  4. Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, NSW, Australia

    • Philip M. Hansbro
  5. Centenary Institute and University of Technology Sydney, Sydney, NSW, 2007, Australia

    • Philip M. Hansbro


  1. Search for Mathew Suji Eapen in:

  2. Search for Pawan Sharma in:

  3. Search for Isobel E. Thompson in:

  4. Search for Wenying Lu in:

  5. Search for Stephen Myers in:

  6. Search for Philip M. Hansbro in:

  7. Search for Sukhwinder Singh Sohal in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Sukhwinder Singh Sohal.

About this article

Publication history