Skip to main content
SpringerLink
Log in

Preclinical Evidence for the Role of Stem/Stromal Cells in COPD

  • Chapter
  • First Online:
Stem Cell-Based Therapy for Lung Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide and there are currently limited treatment options for these patients. The disease is characterized by a reduction in airflow due to chronic bronchitis, as well as airspace enlargement in the distal lung, resulting in a loss of surface area available for gas exchange. At end-stage disease, oxygen therapy and lung transplantation remain the only potential options. The disease is heterogeneous and both inflammatory cells as well as structural cells are thought to play a role in disease onset and progression. Pharmaceutical approaches are ineffective at reversing disease pathology and currently aim only to provide symptomatic relief. A recent area of investigation focuses on exogenous cell therapy, including stem cell administration, and its potential for directing lung regeneration. Cell therapies from a variety of sources, as well as cell-derived products such as extracellular vesicles, have recently shown efficacy in animal models of COPD, but early clinical trials have not yet shown efficacy. In this chapter, we discuss the different animal models of COPD as well as the studies which have been conducted to date with cell therapies. We conclude the chapter with a discussion regarding the limitations of current animal models and discuss potential areas for future study.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Adeloye D, Chua S, Lee CW, Basquill C, Papana A, Theodoratou E, et al. Global and regional estimates of COPD prevalence: systematic review and meta-analysis. J Glob Health. 2015;5(2):186–202. https://doi.org/10.7189/jogh.05.020415.

    Article  Google Scholar 

  2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet (London, England). 2012;380(9859):2095–128. https://doi.org/10.1016/s0140-6736(12)61728-0.

    Article  Google Scholar 

  3. Chapman KR, Mannino DM, Soriano B, Vermeire PA, Buist AS, Thun MJ, et al. Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J. 2006;27(1):188–207. https://doi.org/10.1183/09031936.06.00024505.

    Article  CAS  PubMed  Google Scholar 

  4. Miravitlles M, Ribera A. Understanding the impact of symptoms on the burden of COPD. Respir Res. 2017;18(1):67. https://doi.org/10.1186/s12931-017-0548-3.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2016;138(1):16–27. https://doi.org/10.1016/j.jaci.2016.05.011.

    Article  CAS  PubMed  Google Scholar 

  6. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(7):728–35. https://doi.org/10.1164/rccm.201209-1665OC.

    Article  PubMed  Google Scholar 

  7. Negewo NA, Gibson PG, McDonald VM. COPD and its comorbidities: impact, measurement and mechanisms. Respirology (Carlton, Vic). 2015;20(8):1160–71. https://doi.org/10.1111/resp.12642.

    Article  Google Scholar 

  8. Eisner MD, Anthonisen N, Coultas D, Kuenzli N, Perez-Padilla R, Postma D, et al. An official American Thoracic Society public policy statement: novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182(5):693–718. https://doi.org/10.1164/rccm.200811-1757ST.

    Article  PubMed  Google Scholar 

  9. Sana A, Somda SMA, Meda N, Bouland C. Chronic obstructive pulmonary disease associated with biomass fuel use in women: a systematic review and meta-analysis. BMJ Open Respir Res. 2018;5(1):e000246. https://doi.org/10.1136/bmjresp-2017-000246.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Brandsma CA, de Vries M, Costa R, Woldhuis RR, Konigshoff M, Timens W. Lung ageing and COPD: is there a role for ageing in abnormal tissue repair? Eur Respir Rev. 2017;26(146). https://doi.org/10.1183/16000617.0073-2017.

    Article  PubMed  Google Scholar 

  11. Mercado N, Ito K, Barnes PJ. Accelerated ageing of the lung in COPD: new concepts. Thorax. 2015;70(5):482–9. https://doi.org/10.1136/thoraxjnl-2014-206084.

    Article  PubMed  Google Scholar 

  12. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet (London, England). 2007;370(9589):765–73. https://doi.org/10.1016/S0140-6736(07)61380-4.

    Article  Google Scholar 

  13. Stoller JK, Aboussouan LS. Alpha 1-antitrypsin deficiency. Lancet (London, England). 2005;365(9478):2225–36. https://doi.org/10.1016/S0140-6736(05)66781-5.

    Article  CAS  Google Scholar 

  14. Celedon JC, Lange C, Raby BA, Litonjua AA, Palmer LJ, DeMeo DL, et al. The transforming growth factor-beta 1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD). Hum Mol Genet. 2004;13(15):1649–56. https://doi.org/10.1093/hmg/ddh171.

    Article  CAS  PubMed  Google Scholar 

  15. Keatings VM, Cave SJ, Henry MJ, Morgan K, O’Connor CM, FitzGerald MX, et al. A polymorphism in the tumor necrosis factor-alpha gene promoter region may predispose to a poor prognosis in COPD. Chest. 2000;118(4):971–5. https://doi.org/10.1378/chest.118.4.971.

    Article  CAS  PubMed  Google Scholar 

  16. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet (London, England). 2006;367(9524):1747–57. https://doi.org/10.1016/S0140-6736(06)68770-9.

    Article  Google Scholar 

  17. Mannino DM, Watt G, Hole D, Gillis C, Hart C, McConnachie A, et al. The global burden of chronic obstructive pulmonary disease, number 3, the natural history of chronic obstructive pulmonary disease. Eur Respir J. 2006;27(3):627–43. https://doi.org/10.1183/09031936.06.00024605.

    Article  CAS  PubMed  Google Scholar 

  18. Lundback B, Lindberg A, Lindstrom M, Ronmark E, Jonsson AC, Jonsson E, et al. Not 15 but 50% of smokers develop COPD? Report from the obstructive lung disease in northern Sweden studies. Respir Med. 2003;97(2):115–22. https://doi.org/10.1053/rmed.2003.1446.

    Article  CAS  PubMed  Google Scholar 

  19. Gilliland FD, Li YF, Dubeau L, Berhane K, Avol E, McConnell R, et al. Effects of glutathione S-transferase M1, maternal smoking during pregnancy, and environmental tobacco smoke on asthma and wheezing in children. Am J Respir Crit Care Med. 2002;166(4):457–63. https://doi.org/10.1164/rccm.2112064.

    Article  PubMed  Google Scholar 

  20. Ota C, Baarsma HA, Wagner DE, Hilgendorff A, Königshoff M. Linking bronchopulmonary dysplasia to adult chronic lung diseases: role of WNT signaling. Mol Cell Pediatr. 2016;3(1):34. https://doi.org/10.1186/s40348-016-0062-6.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tashkin DP. Is a long-acting inhaled bronchodilator the first agent to use in stable chronic obstructive pulmonary disease? Curr Opin Pulm Med. 2005;11(2):121–8. https://doi.org/10.1097/00063198-200503000-00004.

    Article  CAS  PubMed  Google Scholar 

  22. Tashkin DP, Simmons MS, Sherrill DL, Coulson AH. Heavy habitual marijuana smoking does not cause an accelerated decline in FEV(1) with age. Am J Respir Crit Care Med. 1997;155(1):141–8. https://doi.org/10.1164/ajrccm.155.1.9001303.

    Article  CAS  PubMed  Google Scholar 

  23. Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc. 2013;10(3):239–47. https://doi.org/10.1513/AnnalsATS.201212-127FR.

    Article  CAS  PubMed  Google Scholar 

  24. Leb JS, D’Souza B, Steiner RM. Marijuana lung. Chronic Obstr Pulm Dis. 2018;5(1):81–3. https://doi.org/10.15326/jcopdf.5.1.2017.0180.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Beshay M, Kaiser H, Niedhart D, Reymond MA, Schmid RA. Emphysema and secondary pneumothorax in young adults smoking cannabis. Eur J Cardiothorac Surg. 2007;32(6):834–8. https://doi.org/10.1016/j.ejcts.2007.07.039.

    Article  PubMed  Google Scholar 

  26. Tashkin DP. Chapter 52 - cannabis smoking and the lung. In: Preedy VR, editor. Handbook of cannabis and related pathologies. San Diego: Academic Press; 2017. p. 494–504.

    Chapter  Google Scholar 

  27. Helyes Z, Kemény Á, Csekő K, Szőke É, Elekes K, Mester M, et al. Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation. Am J Phys Lung Cell Mol Phys. 2017;313(2):L267–L77. https://doi.org/10.1152/ajplung.00354.2016.

    Article  CAS  Google Scholar 

  28. Trupin L, Earnest G, San Pedro M, Balmes JR, Eisner MD, Yelin E, et al. The occupational burden of chronic obstructive pulmonary disease. Eur Respir J. 2003;22(3):462–9. https://doi.org/10.1183/09031936.03.00094203.

    Article  CAS  PubMed  Google Scholar 

  29. Zhong N, Wang C, Yao W, Chen P, Kang J, Huang S, et al. Prevalence of chronic obstructive pulmonary disease in China - a large, population-based survey. Am J Respir Crit Care Med. 2007;176(8):753–60. https://doi.org/10.1164/rccm.200612-17490C.

    Article  PubMed  Google Scholar 

  30. Kelly FJ, Fussell JC. Air pollution and airway disease. Clin Exp Allergy. 2011;41(8):1059–71. https://doi.org/10.1111/j.1365-2222.2011.03776.x.

    Article  CAS  PubMed  Google Scholar 

  31. Schikowski T, Mills IC, Anderson HR, Cohen A, Hansell A, Kauffmann F, et al. Ambient air pollution: a cause of COPD? Eur Respir J. 2014;43(1):250. https://doi.org/10.1183/09031936.00100112.

    Article  PubMed  Google Scholar 

  32. Peacock JL, Anderson HR, Bremner SA, Marston L, Seemungal TA, Strachan DP, et al. Outdoor air pollution and respiratory health in patients with COPD. Thorax. 2011;66(7):591. https://doi.org/10.1136/thx.2010.155358.

    Article  PubMed  Google Scholar 

  33. MacNee W, Donaldson K. Exacerbations of COPD - environmental mechanisms. Chest. 2000;117(5):390s–7s. https://doi.org/10.1378/chest.117.5_suppl_2.390S.

    Article  CAS  PubMed  Google Scholar 

  34. Lippmann M, Thurston GD, Ito K, Reibman J, Xue N, Heikkinen M. Personal exposure to PM of outdoor and indoor origin. Epidemiology. 1999;10(4):S65–S.

    Google Scholar 

  35. Delfino RJ, Becklake MR, Hanley JA. The relationship of urgent hospital admissions for respiratory illnesses to photochemical air-pollution levels in Montreal. Environ Res. 1994;67(1):1–19. https://doi.org/10.1006/enrs.1994.1061.

    Article  CAS  PubMed  Google Scholar 

  36. Løkke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: a 25 year follow up study of the general population. Thorax. 2006;61(11):935–9. https://doi.org/10.1136/thx.2006.062802.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Martinez FD. Early-life origins of chronic obstructive pulmonary disease. N Engl J Med. 2016;375(9):871–8. https://doi.org/10.1056/NEJMra1603287.

    Article  PubMed  Google Scholar 

  38. Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest. 2000;117(2):5–9.

    Article  Google Scholar 

  39. Chung KF, Adcock IM. Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. Eur Respir J. 2008;31(6):1334–56. https://doi.org/10.1183/09031936.00018908.

    Article  CAS  PubMed  Google Scholar 

  40. McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365(17):1567–75. https://doi.org/10.1056/NEJMoa1106955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Barnes PJ. Cellular and molecular mechanisms of asthma and COPD. Clin Sci. 2017;131(13):1541–58. https://doi.org/10.1042/Cs20160487.

    Article  CAS  Google Scholar 

  42. Barnes PJ. Alveolar macrophages in chronic obstructive pulmonary disease (COPD). Cell Mol Biol. 2004;50:627–37.

    Google Scholar 

  43. Morales-Nebreda L, Misharin AV, Perlman H, Budinger RS. The heterogeneity of lung macrophages in the susceptibility to disease. Eur Respir Rev. 2015;24(137):505–9. https://doi.org/10.1183/16000617.0031-2015.

    Article  PubMed  Google Scholar 

  44. Culpitt SV, Rogers DF, Shah P, De Matos C, Russell REK, Donnelly LE, et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;167(1):24–31. https://doi.org/10.1164/rccm.200204-298OC.

    Article  PubMed  Google Scholar 

  45. Russell REK, Thorley A, Culpitt SV, Dodd S, Donnelly LE, Demattos C, et al. Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases. Am J Phys Lung Cell Mol Phys. 2002;283(4):L867–L73. https://doi.org/10.1152/ajplung.00020.2002.

    Article  CAS  Google Scholar 

  46. Vlahos R, Bozinovski S. Role of alveolar macrophages in chronic obstructive pulmonary disease. Front Immunol. 2014;5:435. https://doi.org/10.3389/fimmu.2014.00435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Renda T, Baraldo S, Pelaia G, Bazzan E, Turato G, Papi A, et al. Increased activation of p38 MAPK in COPD. Eur Respir J. 2008;31(1):62–9. https://doi.org/10.1183/09031936.00036707.

    Article  CAS  PubMed  Google Scholar 

  48. Caramori G, Romagnoli M, Casolari P, Bellettato C, Casoni G, Boschetto P, et al. Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax. 2003;58(4):348–51. https://doi.org/10.1136/thorax.58.4.348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Grumelli S, Corry DB, Song LZ, Song L, Green L, Huh J, et al. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. 2004;1(1):75–83. https://doi.org/10.1371/journal.pmed.0010008.

    Article  CAS  Google Scholar 

  50. Fahy JV, Dickey BF. Airway mucus function and dysfunction REPLY. N Engl J Med. 2011;364(10):978.

    Article  CAS  Google Scholar 

  51. Ballarin A, Bazzan E, Zenteno RH, Turato G, Baraldo S, Zanovello D, et al. Mast cell infiltration discriminates between histopathological phenotypes of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(3):233–9. https://doi.org/10.1164/rccm.201112-2142OC.

    Article  PubMed  Google Scholar 

  52. Beckett EL, Stevens RL, Jarnicki AG, Kim RY, Hanish I, Hansbro NG, et al. A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis. J Allergy Clin Immunol. 2013;131(3):752–62.e7. https://doi.org/10.1016/j.jaci.2012.11.053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Andersson CK, Mori M, Bjermer L, Löfdahl C-G, Erjefält JS. Alterations in lung mast cell populations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181(3):206–17. https://doi.org/10.1164/rccm.200906-0932OC.

    Article  PubMed  Google Scholar 

  54. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–53. https://doi.org/10.1056/NEJMoa032158.

    Article  CAS  PubMed  Google Scholar 

  55. Di Stefano A, Caramori G, Gnemmi I, Contoli M, Vicari C, Capelli A, et al. T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients. Clin Exp Immunol. 2009;157(2):316–24. https://doi.org/10.1111/j.1365-2249.2009.03965.x.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Pridgeon C, Bugeon L, Donnelly L, Straschil U, Tudhope SJ, Fenwick P, et al. Regulation of IL-17 in chronic inflammation in the human lung. Clin Sci. 2011;120(11–12):515–24. https://doi.org/10.1042/Cs20100417.

    Article  Google Scholar 

  57. Artis D, Spits H. The biology of innate lymphoid cells. Nature. 2015;517(7534):293–301. https://doi.org/10.1038/nature14189.

    Article  CAS  PubMed  Google Scholar 

  58. De Grove KC, Provoost S, Verhamme FM, Bracke KR, Joos GF, Maes T et al. Characterization and quantification of innate lymphoid cell subsets in human lung. PLoS One. 2016;11(1). ARTN e0145961. https://doi.org/10.1371/journal.pone.0145961.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest. 2013;144(1):266–73. https://doi.org/10.1378/chest.12-2664.

    Article  CAS  PubMed  Google Scholar 

  60. Malhotra D, Thimmulappa R, Singh A, Acien-Navas A, Elliot M, Hogg J et al. Decline in NRF2-regulated antioxidant pathway in advanced COPD patient lungs due to DJ-1 deficit. FASEB J. 2008;22.

    Google Scholar 

  61. Stockley RA. The role of proteinases in the pathogenesis of chronic-bronchitis. Am J Respir Crit Care Med. 1994;150(6):S109–S13. https://doi.org/10.1164/ajrccm/150.6_Pt_2.S109.

    Article  CAS  PubMed  Google Scholar 

  62. Shapiro SD. Elastolytic metalloproteinases produced by human mononuclear phagocytes - potential roles in destructive lung-disease. Am J Respir Crit Care Med. 1994;150(6):S160–S4. https://doi.org/10.1164/ajrccm/150.6_Pt_2.S160.

    Article  CAS  PubMed  Google Scholar 

  63. Löffek S, Schilling O, Franzke CW. Biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011;38(1):191. https://doi.org/10.1183/09031936.00146510.

    Article  CAS  PubMed  Google Scholar 

  64. Sato A, Hirai T, Imura A, Kita N, Iwano A, Muro S, et al. Morphological mechanism of the development of pulmonary emphysema in klotho mice. Proc Natl Acad Sci U S A. 2007;104(7):2361–5. https://doi.org/10.1073/pnas.0607882104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Black JL, Burgess JK, Johnson PRA. Airway smooth muscle—its relationship to the extracellular matrix. Respir Physiol Neurobiol. 2003;137(2):339–46. https://doi.org/10.1016/S1569-9048(03)00157-5.

    Article  CAS  PubMed  Google Scholar 

  66. Finlay GA, ODriscoll LR, Russell KJ, DArcy EM, Masterson JB, Fitzgerald MX, et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med. 1997;156(1):240–7. https://doi.org/10.1164/ajrccm.156.1.9612018.

    Article  CAS  PubMed  Google Scholar 

  67. Shapiro SD, Kobayashi DK, Ley TJ. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J Biol Chem. 1993;268(32):23824–9.

    CAS  PubMed  Google Scholar 

  68. Sallenave JM, Shulmann J, Crossley J, Jordana M, Gauldie J. Regulation of secretory leukocyte proteinase-inhibitor (Slpi) and elastase-specific inhibitor (Esi/Elafin) in human airway epithelial-cells by cytokines and neutrophilic enzymes. Am J Resp Cell Mol. 1994;11(6):733–41. https://doi.org/10.1165/ajrcmb.11.6.7946401.

    Article  CAS  Google Scholar 

  69. Gan WQ, Man SFP, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59(7):574–80. https://doi.org/10.1136/thx.2003.019588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Agusti A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012;7(5). https://doi.org/10.1371/journal.pone.0037483.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Hurst JR, Donaldson GC, Perera WR, Wilkinson TMA, Bilello JA, Hagan GW, et al. Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;174(8):867–74. https://doi.org/10.1164/rccm.200604-506OC.

    Article  CAS  PubMed  Google Scholar 

  72. Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(10):982–8. https://doi.org/10.1164/rccm.201206-1113OC.

    Article  CAS  PubMed  Google Scholar 

  73. Cavaillès A, Brinchault-Rabin G, Dixmier A, Goupil F, Gut-Gobert C, Marchand-Adam S, et al. Comorbidities of COPD. Eur Respir Rev. 2013;22(130):454. https://doi.org/10.1183/09059180.00008612.

    Article  PubMed  Google Scholar 

  74. Arai N, Kondo M, Izumo T, Tamaoki J, Nagai A. Inhibition of neutrophil elastase-induced goblet cell metaplasia by tiotropium in mice. Eur Respir J. 2010;35(5):1164. https://doi.org/10.1183/09031936.00040709.

    Article  CAS  PubMed  Google Scholar 

  75. Burgel PR, Nadel JA. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax. 2004;59(11):992–6. https://doi.org/10.1136/thx.2003.018879.

    Article  PubMed  PubMed Central  Google Scholar 

  76. de Boer WI, van Schadewijk A, Sont JK, Sharma HS, Stolk J, Hiemstra PS, et al. Transforming growth factor beta(1) and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;158(6):1951–7. https://doi.org/10.1164/ajrccm.158.6.9803053.

    Article  PubMed  Google Scholar 

  77. Fagan KA, McMurtry IF, Rodman DM. Role of endothelin-1 in lung disease. Respir Res. 2001;2(2):90–101. https://doi.org/10.1186/rr44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Galban CJ, Han MLK, Boes JL, Chughtai KA, Meyer CR, Johnson TD, et al. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat Med. 2012;18(11):1711-+. https://doi.org/10.1038/nm.2971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Derrico A, Scarani P, Colosimo E, Spina M, Grigioni WF, Mancini AM. Changes in the alveolar connective-tissue of the aging lung - an immunohistochemical study. Virchows Arch A. 1989;415(2):137–44. https://doi.org/10.1007/Bf00784351.

    Article  CAS  Google Scholar 

  80. Frette C, Jacob MP, Wei SM, Bertrand JP, Laurent P, Kauffmann F, et al. Relationship of serum elastin peptide level to single breath transfer factor for carbon monoxide in French coal miners. Thorax. 1997;52(12):1045–50. https://doi.org/10.1136/thx.52.12.1045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Jones RL, Noble PB, Elliot JG, James AL. Airway remodelling in COPD: It’s not asthma! Respirology (Carlton, Vic). 2016;21(8):1347–56. https://doi.org/10.1111/resp.12841.

    Article  Google Scholar 

  82. Burgess JK, Mauad T, Tjin G, Karlsson JC, Westergren-Thorsson G. The extracellular matrix - the under-recognized element in lung disease? J Pathol. 2016;240(4):397–409. https://doi.org/10.1002/path.4808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tjin G, Xu P, Kable SH, Kable EPW, Burgess JK. Quantification of collagen I in airway tissues using second harmonic generation. J Biomed Opt. 2014;19(3). https://doi.org/10.1117/1.Jbo.19.3.036005.

    Article  Google Scholar 

  84. Black PN, Ching PST, Beaumont B, Ranasinghe S, Taylor G, Merrilees MJ. Changes in elastic fibres in the small airways and alveoli in COPD. Eur Respir J. 2008;31(5):998–1004. https://doi.org/10.1183/09031936.00017207.

    Article  CAS  PubMed  Google Scholar 

  85. Navratilova Z, Kolek V, Petrek M. Matrix metalloproteinases and their inhibitors in chronic obstructive pulmonary disease. Arch Immunol Ther Ex. 2016;64(3):177–93. https://doi.org/10.1007/s00005-015-0375-5.

    Article  CAS  Google Scholar 

  86. Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley DG, Marconcini LA, et al. Elastin fragments drive disease progression in a murine model of emphysema. J Clin Invest. 2006;116(3):753–9. https://doi.org/10.1172/Jci25617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sand JM, Martinez G, Midjord AK, Karsdal MA, Leeming DJ, Lange P. Characterization of serological neo-epitope biomarkers reflecting collagen remodeling in clinically stable chronic obstructive pulmonary disease. Clin Biochem. 2016;49(15):1144–51. https://doi.org/10.1016/j.clinbiochem.2016.09.003.

    Article  CAS  PubMed  Google Scholar 

  88. Sand JMB, Knox AJ, Lange P, Sun S, Kristensen JH, Leeming DJ, et al. Accelerated extracellular matrix turnover during exacerbations of COPD. Respir Res. 2015;16(1):69. https://doi.org/10.1186/s12931-015-0225-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bihlet AR, Karsdal MA, Sand JMB, Leeming DJ, Roberts M, White W, et al. Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD. Respir Res. 2017;18(1):22. https://doi.org/10.1186/s12931-017-0509-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sand JMB, Leeming DJ, Byrjalsen I, Bihlet AR, Lange P, Tal-Singer R, et al. High levels of biomarkers of collagen remodeling are associated with increased mortality in COPD – results from the ECLIPSE study. Respir Res. 2016;17(1):125. https://doi.org/10.1186/s12931-016-0440-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Burgess JK, Weckmann M. Matrikines and the lungs. Pharmacol Ther. 2012;134(3):317–37. https://doi.org/10.1016/j.pharmthera.2012.02.002.

    Article  CAS  PubMed  Google Scholar 

  92. Brandsma CA, van den Berge M, Postma DS, Jonker MR, Brouwer S, Pare PD, et al. A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD. Thorax. 2015;70(1):21–32. https://doi.org/10.1136/thoraxjnl-2014-205091.

    Article  PubMed  Google Scholar 

  93. Wagner DE, Bonenfant NR, Parsons CS, Sokocevic D, Brooks EM, Borg ZD, et al. Comparative decellularization and recellularization of normal versus emphysematous human lungs. Biomaterials. 2014;35(10):3281–97. https://doi.org/10.1016/j.biomaterials.2013.12.103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen XJ, Song XM, Yue W, Chen DS, Yu J, Yao Z, et al. Fibulin-5 inhibits Wnt/beta-catenin signaling in lung cancer. Oncotarget. 2015;6(17):15022–34. https://doi.org/10.18632/oncotarget.3609.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Larsson-Callerfelt AK, Hallgren O, Andersson-Sjoland A, Thiman L, Bjorklund J, Kron J et al. Defective alterations in the collagen network to prostacyclin in COPD lung fibroblasts. Respir Res. 2013;14. https://doi.org/10.1186/1465-9921-14-21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Barnes PJ. Senescence in COPD and its comorbidities. Annu Rev Physiol. 2017;79:517–39. https://doi.org/10.1146/annurev-physiol-022516-034314.

    Article  CAS  PubMed  Google Scholar 

  97. Birch J, Anderson RK, Correia-Melo C, Jurk D, Hewitt G, Marques FM, et al. DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. Am J Phys Lung Cell Mol Phys. 2015;309(10):L1124–L37. https://doi.org/10.1152/ajplung.00293.2015.

    Article  CAS  Google Scholar 

  98. Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev. 2014;28(2):99–114. https://doi.org/10.1101/gad.235184.113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Miller AJ, Spence JR. In vitro models to study human lung development, disease and homeostasis. Physiology. 2017;32(3):246–60. https://doi.org/10.1152/physiol.00041.2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Crosby LM, Waters CM. Epithelial repair mechanisms in the lung. Am J Phys Lung Cell Mol Phys. 2010;298(6):L715–L31. https://doi.org/10.1152/ajplung.00361.2009.

    Article  CAS  Google Scholar 

  101. Staudt MR, Buro-Auriemma LJ, Walters MS, Salit J, Vincent T, Shaykhiev R, et al. Airway basal stem/progenitor cells have diminished capacity to regenerate airway epithelium in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;190(8):955–8. https://doi.org/10.1164/rccm.201406-1167LE.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, et al. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest. 2013;123(7):3025–36. https://doi.org/10.1172/Jci68782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kotton DN, Morrisey EE. Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med. 2014;20(8):822–32. https://doi.org/10.1038/nm.3642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kruk DMLW, Heijink IH, Slebos D-J, Timens W, Ten Hacken NH. Mesenchymal stromal cells to regenerate emphysema: on the horizon? Respiration. 2018;96(2):148–58. https://doi.org/10.1159/000488149.

    Article  PubMed  Google Scholar 

  105. Hoffman AM, Paxson JA, Mazan MR, Davis AM, Tyagi S, Murthy S, et al. Lung-derived mesenchymal stromal cell post-transplantation survival, persistence, paracrine expression, and repair of elastase-injured lung. Stem Cells Dev. 2011;20(10):1779–92. https://doi.org/10.1089/scd.2011.0105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Palange P, Testa U, Huertas A, Calabro L, Antonucci R, Petrucci E, et al. Circulating haemopoietic and endothelial progenitor cells are decreased in COPD. Eur Respir J. 2006;27(3):529–41. https://doi.org/10.1183/09031936.06.00120604.

    Article  CAS  PubMed  Google Scholar 

  107. Skronska-Wasek W, Mutze K, Baarsma HA, Bracke KR, Alsafadi HN, Lehmann M, et al. Reduced frizzled receptor 4 expression prevents WNT/β-catenin–driven alveolar lung repair in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196(2):172–85. https://doi.org/10.1164/rccm.201605-0904OC.

    Article  CAS  PubMed  Google Scholar 

  108. Tura-Ceide O, Lobo B, Paul T, Puig-Pey R, Coll-Bonfill N, Garcia-Lucio J et al. Cigarette smoke challenges bone marrow mesenchymal stem cell capacities in guinea pig. Respir Res. 2017;18. https://doi.org/10.1186/s12931-017-0530-0.

  109. Fujino N, Ota C, Takahashi T, Suzuki T, Suzuki S, Yamada M et al. Gene expression profiles of alveolar type II cells of chronic obstructive pulmonary disease: a case-control study. BMJ Open. 2012;2(6). https://doi.org/10.1136/bmjopen-2012-001553.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Ravnic DJ, Konerding MA, Pratt JP, Wolloscheck T, Huss HT, Mentzer SJ. The murine bronchopulmonary microcirculation in hapten-induced inflammation. J Thorac Cardiovasc Surg. 2007;133(1):97–103. https://doi.org/10.1016/j.jtcvs.2006.08.054.

    Article  PubMed  Google Scholar 

  111. Kobayashi S, Fujinawa R, Ota F, Kobayashi S, Angata T, Ueno M, et al. A single dose of lipopolysaccharide into mice with emphysema mimics human chronic obstructive pulmonary disease exacerbation as assessed by micro-computed tomography. Am J Respir Cell Mol Biol. 2013;49(6):971–7. https://doi.org/10.1165/rcmb.2013-0074OC.

    Article  CAS  PubMed  Google Scholar 

  112. Spond J, Billah MM, Chapman RW, Egan RW, Hey JA, House A, et al. The role of neutrophils in LPS-induced changes in pulmonary function in conscious rats. Pulm Pharmacol Ther. 2004;17(3):133–40. https://doi.org/10.1016/j.pupt.2004.01.003.

    Article  CAS  PubMed  Google Scholar 

  113. Rogers DF, Jeffery PK. Inhibition by oral N-acetylcysteine of cigarette smoke-induced “bronchitis” in the rat. Exp Lung Res. 1986;10(3):267–83.

    Article  CAS  PubMed  Google Scholar 

  114. Depuydt P, Joos GF, Pauwels RA. Ambient ozone concentrations induce airway hyperresponsiveness in some rat strains. Eur Respir J. 1999;14(1):125–31.

    Article  CAS  PubMed  Google Scholar 

  115. March TH, Barr EB, Finch GL, Hahn FF, Hobbs CH, Menache MG, et al. Cigarette smoke exposure produces more evidence of emphysema in B6C3F1 mice than in F344 rats. Toxicol Sci. 1999;51(2):289–99.

    Article  CAS  PubMed  Google Scholar 

  116. Cavarra E, Bartalesi B, Lucattelli M, Fineschi S, Lunghi B, Gambelli F, et al. Effects of cigarette smoke in mice with different levels of alpha(1)-proteinase inhibitor and sensitivity to oxidants. Am J Respir Crit Care Med. 2001;164(5):886–90. https://doi.org/10.1164/ajrccm.164.5.2010032.

    Article  CAS  PubMed  Google Scholar 

  117. March TH, Bowen LE, Finch GL, Nikula KJ, Wayne BJ, Hobbs CH. Effects of strain and treatment with inhaled aII-trans-retinoic acid on cigarette smoke-induced pulmonary emphysema in mice. COPD. 2005;2(3):289–302.

    Article  PubMed  Google Scholar 

  118. Garcia-Arcos I, Geraghty P, Baumlin N, Campos M, Dabo AJ, Jundi B, et al. Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner. Thorax. 2016;71(12):1119. https://doi.org/10.1136/thoraxjnl-2015-208039.

    Article  PubMed  Google Scholar 

  119. Sussan TE, Gajghate S, Thimmulappa RK, Ma J, Kim JH, Sudini K, et al. Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model. PLoS One. 2015;10(2):e0116861. https://doi.org/10.1371/journal.pone.0116861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bellofiore S, Eidelman DH, Macklem PT, Martin JG. Effects of elastase-induced emphysema on airway responsiveness to methacholine in rats. J Appl Physiol (Bethesda, Md: 1985). 1989;66(2):606–12. https://doi.org/10.1152/jappl.1989.66.2.606.

    Article  CAS  Google Scholar 

  121. Meshi B, Vitalis TZ, Ionescu D, Elliott WM, Liu C, Wang XD, et al. Emphysematous lung destruction by cigarette smoke. The effects of latent adenoviral infection on the lung inflammatory response. Am J Respir Cell Mol Biol. 2002;26(1):52–7. https://doi.org/10.1165/ajrcmb.26.1.4253.

    Article  CAS  PubMed  Google Scholar 

  122. Wright JL, Churg A. Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig. Am Rev Respir Dis. 1990;142(6 Pt 1):1422–8. https://doi.org/10.1164/ajrccm/142.6_Pt_1.1422.

    Article  CAS  PubMed  Google Scholar 

  123. Bernfeld P, Homburger F, Soto E, Pai KJ. Cigarette smoke inhalation studies in inbred Syrian golden hamsters. J Natl Cancer Inst. 1979;63(3):675–89.

    Article  CAS  PubMed  Google Scholar 

  124. Stolk J, Rudolphus A, Davies P, Osinga D, Dijkman JH, Agarwal L, et al. Induction of emphysema and bronchial mucus cell hyperplasia by intratracheal instillation of lipopolysaccharide in the hamster. J Pathol. 1992;167(3):349–56. https://doi.org/10.1002/path.1711670314.

    Article  CAS  PubMed  Google Scholar 

  125. Park SS, Kikkawa Y, Goldring IP, Daly MM, Zelefsky M, Shim C, et al. An animal model of cigarette smoking in beagle dogs: correlative evaluation of effects on pulmonary function, defense, and morphology. Am Rev Respir Dis. 1977;115(6):971–9. https://doi.org/10.1164/arrd.1977.115.6.971.

    Article  CAS  PubMed  Google Scholar 

  126. Raju SV, Kim H, Byzek SA, Tang LP, Trombley JE, Jackson P et al. A ferret model of COPD-related chronic bronchitis. JCI Insight. 2016;1(15). https://doi.org/10.1172/jci.insight.87536.

  127. Martorana PA, van Even P, Gardi C, Lungarella G. A 16-month study of the development of genetic emphysema in tight-skin mice. Am Rev Respir Dis. 1989;139(1):226–32. https://doi.org/10.1164/ajrccm/139.1.226.

    Article  CAS  PubMed  Google Scholar 

  128. Ito S, Bartolak-Suki E, Shipley JM, Parameswaran H, Majumdar A, Suki B. Early emphysema in the tight skin and pallid mice: roles of microfibril-associated glycoproteins, collagen, and mechanical forces. Am J Respir Cell Mol Biol. 2006;34(6):688–94. https://doi.org/10.1165/rcmb.2006-0002OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Keil M, Lungarella G, Cavarra E, van Even P, Martorana PA. A scanning electron microscopic investigation of genetic emphysema in tight-skin, pallid, and beige mice, three different C57 BL/6J mutants. Lab Invest. 1996;74(2):353–62.

    CAS  PubMed  Google Scholar 

  130. Mercer JF, Grimes A, Ambrosini L, Lockhart P, Paynter JA, Dierick H, et al. Mutations in the murine homologue of the Menkes gene in dappled and blotchy mice. Nat Genet. 1994;6(4):374–8. https://doi.org/10.1038/ng0494-374.

    Article  CAS  PubMed  Google Scholar 

  131. Shibata Y, Zsengeller Z, Otake K, Palaniyar N, Trapnell BC. Alveolar macrophage deficiency in osteopetrotic mice deficient in macrophage colony-stimulating factor is spontaneously corrected with age and associated with matrix metalloproteinase expression and emphysema. Blood. 2001;98(9):2845–52.

    Article  CAS  PubMed  Google Scholar 

  132. Bostrom H, Willetts K, Pekny M, Leveen P, Lindahl P, Hedstrand H, et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell. 1996;85(6):863–73.

    Article  CAS  PubMed  Google Scholar 

  133. Weinstein M, Xu X, Ohyama K, Deng CX. FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. Development. 1998;125(18):3615–23.

    CAS  PubMed  Google Scholar 

  134. Nakamura T, Lozano PR, Ikeda Y, Iwanaga Y, Hinek A, Minamisawa S, et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature. 2002;415(6868):171–5. https://doi.org/10.1038/415171a.

    Article  CAS  PubMed  Google Scholar 

  135. Wendel DP, Taylor DG, Albertine KH, Keating MT, Li DY. Impaired distal airway development in mice lacking elastin. Am J Respir Cell Mol Biol. 2000;23(3):320–6. https://doi.org/10.1165/ajrcmb.23.3.3906.

    Article  CAS  PubMed  Google Scholar 

  136. McGowan S, Jackson SK, Jenkins-Moore M, Dai HH, Chambon P, Snyder JM. Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers. Am J Respir Cell Mol Biol. 2000;23(2):162–7. https://doi.org/10.1165/ajrcmb.23.2.3904.

    Article  CAS  PubMed  Google Scholar 

  137. Kalinichenko VV, Lim L, Stolz DB, Shin B, Rausa FM, Clark J, et al. Defects in pulmonary vasculature and perinatal lung hemorrhage in mice heterozygous null for the forkhead box f1 transcription factor. Dev Biol. 2001;235(2):489–506. https://doi.org/10.1006/dbio.2001.0322.

    Article  CAS  PubMed  Google Scholar 

  138. Zhao J, Chen H, Peschon JJ, Shi W, Zhang Y, Frank SJ, et al. Pulmonary hypoplasia in mice lacking tumor necrosis factor-alpha converting enzyme indicates an indispensable role for cell surface protein shedding during embryonic lung branching morphogenesis. Dev Biol. 2001;232(1):204–18. https://doi.org/10.1006/dbio.2001.0176.

    Article  CAS  PubMed  Google Scholar 

  139. Quaggin SE, Schwartz L, Cui S, Igarashi P, Deimling J, Post M, et al. The basic-helix-loop-helix protein pod1 is critically important for kidney and lung organogenesis. Development. 1999;126(24):5771–83.

    CAS  PubMed  Google Scholar 

  140. Leco KJ, Waterhouse P, Sanchez OH, Gowing KL, Poole AR, Wakeham A, et al. Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). J Clin Invest. 2001;108(6):817–29. https://doi.org/10.1172/jci12067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Yoshida M, Korfhagen TR, Whitsett JA. Surfactant protein D regulates NF-kappa B and matrix metalloproteinase production in alveolar macrophages via oxidant-sensitive pathways. J Immunol. 2001;166(12):7514–9.

    Article  CAS  PubMed  Google Scholar 

  142. Goss AM, Tian Y, Tsukiyama T, Cohen ED, Zhou D, Lu MM, et al. Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Dev Cell. 2009;17(2):290–8. https://doi.org/10.1016/j.devcel.2009.06.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Caprioli A, Villasenor A, Wylie LA, Braitsch C, Marty-Santos L, Barry D, et al. Wnt4 is essential to normal mammalian lung development. Dev Biol. 2015;406(2):222–34. https://doi.org/10.1016/j.ydbio.2015.08.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Li C, Xiao J, Hormi K, Borok Z, Minoo P. Wnt5a participates in distal lung morphogenesis. Dev Biol. 2002;248(1):68–81.

    Article  CAS  PubMed  Google Scholar 

  145. Li C, Hu L, Xiao J, Chen H, Li JT, Bellusci S, et al. Wnt5a regulates Shh and Fgf10 signaling during lung development. Dev Biol. 2005;287(1):86–97. https://doi.org/10.1016/j.ydbio.2005.08.035.

    Article  CAS  PubMed  Google Scholar 

  146. Rajagopal J, Carroll TJ, Guseh JS, Bores SA, Blank LJ, Anderson WJ, et al. Wnt7b stimulates embryonic lung growth by coordinately increasing the replication of epithelium and mesenchyme. Development. 2008;135(9):1625–34. https://doi.org/10.1242/dev.015495.

    Article  CAS  PubMed  Google Scholar 

  147. Harris-Johnson KS, Domyan ET, Vezina CM, Sun X. Beta-catenin promotes respiratory progenitor identity in mouse foregut. Proc Natl Acad Sci U S A. 2009;106(38):16287–92. https://doi.org/10.1073/pnas.0902274106.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Zacchigna L, Vecchione C, Notte A, Cordenonsi M, Dupont S, Maretto S, et al. Emilin1 links TGF-beta maturation to blood pressure homeostasis. Cell. 2006;124(5):929–42. https://doi.org/10.1016/j.cell.2005.12.035.

    Article  CAS  PubMed  Google Scholar 

  149. Mitani A, Nagase T, Fukuchi K, Aburatani H, Makita R, Kurihara H. Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice. Am J Respir Crit Care Med. 2009;180(4):326–38. https://doi.org/10.1164/rccm.200812-1827OC.

    Article  CAS  PubMed  Google Scholar 

  150. Ray P, Tang W, Wang P, Homer R, Kuhn C 3rd, Flavell RA, et al. Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes. J Clin Invest. 1997;100(10):2501–11. https://doi.org/10.1172/jci119792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Hoyle GW, Li J, Finkelstein JB, Eisenberg T, Liu JY, Lasky JA, et al. Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice overexpressing platelet-derived growth factor. Am J Pathol. 1999;154(6):1763–75. https://doi.org/10.1016/s0002-9440(10)65432-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Sokocevic D, Bonenfant NR, Wagner DE, Borg ZD, Lathrop MJ, Lam YW, et al. The effect of age and emphysematous and fibrotic injury on the re-cellularization of de-cellularized lungs. Biomaterials. 2013;34(13):3256–69. https://doi.org/10.1016/j.biomaterials.2013.01.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Hedström U, Hallgren O, Öberg L, DeMicco A, Vaarala O, Westergren-Thorsson G, et al. Bronchial extracellular matrix from COPD patients induces altered gene expression in repopulated primary human bronchial epithelial cells. Sci Rep. 2018;8(1):3502. https://doi.org/10.1038/s41598-018-21727-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Sun Z, Li F, Zhou X, Chung KF, Wang W, Wang J. Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical studies and clinical trials. J Thorac Dis. 2018;10(2):1084–98. https://doi.org/10.21037/jtd.2018.01.46.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Katsha AM, Ohkouchi S, Xin H, Kanehira M, Sun R, Nukiwa T, et al. Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. Mol Ther. 2011;19(1):196–203. https://doi.org/10.1038/mt.2010.192.

    Article  CAS  PubMed  Google Scholar 

  156. Antunes MA, Abreu SC, Cruz FF, Teixeira AC, Lopes-Pacheco M, Bandeira E, et al. Effects of different mesenchymal stromal cell sources and delivery routes in experimental emphysema. Respir Res. 2014;15:118. https://doi.org/10.1186/s12931-014-0118-x.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Tibboel J, Keijzer R, Reiss I, de Jongste JC, Post M. Intravenous and intratracheal mesenchymal stromal cell injection in a mouse model of pulmonary emphysema. COPD. 2014;11(3):310–8. https://doi.org/10.3109/15412555.2013.854322.

    Article  PubMed  Google Scholar 

  158. Chen YB, Lan YW, Chen LG, Huang TT, Choo KB, Cheng WT, et al. Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol alleviates elastase-induced emphysema in a mouse model. Cell Stress Chaperones. 2015;20(6):979–89. https://doi.org/10.1007/s12192-015-0627-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Shiraishi K, Shichino S, Tsukui T, Hashimoto S, Ueha S, Matsushima K. Engraftment and proliferation potential of embryonic lung tissue cells in irradiated mice with emphysema. Sci Rep. 2019;9(1):3657. https://doi.org/10.1038/s41598-019-40237-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Ghorbani A, Feizpour A, Hashemzahi M, Gholami L, Hosseini M, Soukhtanloo M, et al. The effect of adipose derived stromal cells on oxidative stress level, lung emphysema and white blood cells of guinea pigs model of chronic obstructive pulmonary disease. Daru. 2014;22(1):26. https://doi.org/10.1186/2008-2231-22-26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Feizpour A, Boskabady MH, Ghorbani A, Peter Di Y. Adipose-derived stromal cell therapy affects lung inflammation and tracheal responsiveness in guinea pig model of COPD. PLoS One. 2014;9(10):e108974. https://doi.org/10.1371/journal.pone.0108974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Shigemura N, Okumura M, Mizuno S, Imanishi Y, Nakamura T, Sawa Y. Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema. Am J Transplant. 2006;6(11):2592–600. https://doi.org/10.1111/j.1600-6143.2006.01522.x.

    Article  CAS  PubMed  Google Scholar 

  163. Zhen G, Liu H, Gu N, Zhang H, Xu Y, Zhang Z. Mesenchymal stem cells transplantation protects against rat pulmonary emphysema. Front Biosci. 2008;13:3415–22. https://doi.org/10.2741/2936.

    Article  CAS  PubMed  Google Scholar 

  164. Zhen G, Xue Z, Zhao J, Gu N, Tang Z, Xu Y, et al. Mesenchymal stem cell transplantation increases expression of vascular endothelial growth factor in papain-induced emphysematous lungs and inhibits apoptosis of lung cells. Cytotherapy. 2010;12(5):605–14. https://doi.org/10.3109/14653241003745888.

    Article  CAS  PubMed  Google Scholar 

  165. Huh JW, Kim SY, Lee JH, Lee JS, Van Ta Q, Kim M, et al. Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am J Physiol Lung Cell Mol Physiol. 2011;301(3):L255–66. https://doi.org/10.1152/ajplung.00253.2010.

    Article  CAS  PubMed  Google Scholar 

  166. Furuya N, Takenaga M, Ohta Y, Tokura Y, Hamaguchi A, Sakamaki A, et al. Cell therapy with adipose tissue-derived stem/stromal cells for elastase-induced pulmonary emphysema in rats. Regen Med. 2012;7(4):503–12. https://doi.org/10.2217/rme.12.25.

    Article  CAS  PubMed  Google Scholar 

  167. Guan XJ, Song L, Han FF, Cui ZL, Chen X, Guo XJ, et al. Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors. J Cell Biochem. 2013;114(2):323–35. https://doi.org/10.1002/jcb.24377.

    Article  CAS  PubMed  Google Scholar 

  168. Li Y, Gu C, Xu W, Yan J, Xia Y, Ma Y, Chen C, He X, Tao H. Therapeutic effects of amniotic fluid-derived mesenchymal stromal cells on lung injury in rats with emphysema. Respir Res. 2014;15(1):120. https://doi.org/10.1186/s12931-014-0120-3.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Zhang W-G, He L, Shi X-M, Wu S-S, Zhang B, Mei L, Xu Y-J, Zhang Z-X, Zhao J-P, Zhang H-L. Regulation of transplanted mesenchymal stem cells by the lung progenitor niche in rats with chronic obstructive pulmonary disease. Respir Res. 2014;15(1):33. https://doi.org/10.1186/1465-9921-15-33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Zhao Y, Xu A, Xu Q, Zhao W, Li D, Fang X, et al. Bone marrow mesenchymal stem cell transplantation for treatment of emphysemic rats. Int J Clin Exp Med. 2014;7(4):968–72.

    PubMed  PubMed Central  Google Scholar 

  171. Gu W, Song L, Li XM, Wang D, Guo XJ, Xu WG. Mesenchymal stem cells alleviate airway inflammation and emphysema in COPD through down-regulation of cyclooxygenase-2 via p38 and ERK MAPK pathways. Sci Rep. 2015;5:8733. https://doi.org/10.1038/srep08733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Yuhgetsu H, Ohno Y, Funaguchi N, Asai T, Sawada M, Takemura G, et al. Beneficial effects of autologous bone marrow mononuclear cell transplantation against elastase-induced emphysema in rabbits. Exp Lung Res. 2006;32(9):413–26. https://doi.org/10.1080/01902140601047633.

    Article  PubMed  Google Scholar 

  173. Kim YS, Kim JY, Huh JW, Lee SW, Choi SJ, Oh YM. The therapeutic effects of optimal dose of mesenchymal stem cells in a murine model of an elastase induced-emphysema. Tuberc Respir Dis. 2015;78(3):239–45. https://doi.org/10.4046/trd.2015.78.3.239.

    Article  Google Scholar 

  174. Peron JP, de Brito AA, Pelatti M, Brandao WN, Vitoretti LB, Greiffo FR, et al. Human tubal-derived mesenchymal stromal cells associated with low level laser therapy significantly reduces cigarette smoke-induced COPD in C57BL/6 mice. PLoS One. 2015;10(8):e0136942. https://doi.org/10.1371/journal.pone.0136942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Schweitzer KS, Johnstone BH, Garrison J, Rush NI, Cooper S, Traktuev DO, et al. Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking. Am J Respir Crit Care Med. 2011;183(2):215–25. https://doi.org/10.1164/rccm.201001-0126OC.

    Article  PubMed  Google Scholar 

  176. Li X, Zhang Y, Yeung SC, Liang Y, Liang X, Ding Y, et al. Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage. Am J Respir Cell Mol Biol. 2014;51(3):455–65. https://doi.org/10.1165/rcmb.2013-0529OC.

    Article  CAS  PubMed  Google Scholar 

  177. Kim Y-S, Kim J-Y, Cho R, Shin D-M, Lee SW, Oh Y-M. Adipose stem cell-derived nanovesicles inhibit emphysema primarily via an FGF2-dependent pathway. Exp Mol Med. 2017;49:e284. https://doi.org/10.1038/emm.2016.127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Rosen C, Shezen E, Aronovich A, Klionsky YZ, Yaakov Y, Assayag M, et al. Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice. Nat Med. 2015;21:869. https://doi.org/10.1038/nm.3889.

    Article  CAS  PubMed  Google Scholar 

  179. Butler JP, Loring SH, Patz S, Tsuda A, Yablonskiy DA, Mentzer SJ. Evidence for adult lung growth in humans. N Engl J Med. 2012;367(3):244–7. https://doi.org/10.1056/NEJMoa1203983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Phillips B, Shaw J, Turco L, McDonald D, Carey J, Balters M, et al. Traumatic pulmonary pseudocyst: an underreported entity. Injury. 2017;48(2):214–20. https://doi.org/10.1016/j.injury.2016.12.006.

    Article  CAS  PubMed  Google Scholar 

  181. Bermejo-Martin JF, Martin-Fernandez M, Lopez-Mestanza C, Duque P, Almansa R. Shared features of endothelial dysfunction between sepsis and its preceding risk factors (aging and chronic disease). J Clin Med. 2018;7(11). https://doi.org/10.3390/jcm7110400.

    Article  CAS  PubMed Central  Google Scholar 

  182. Uhl FE, Vierkotten S, Wagner DE, Burgstaller G, Costa R, Koch I, et al. Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures. Eur Respir J. 2015;46(4):1150–66. https://doi.org/10.1183/09031936.00183214.

    Article  CAS  PubMed  Google Scholar 

  183. Verloop MC. On the arteriae bronchiales and their anastomosing with the arteria pulmonalis in some rodents; a micro-anatomical study. Acta Anat. 1949;7(1–2):1–32.

    Article  CAS  PubMed  Google Scholar 

  184. Irvin CG, Bates JH. Measuring the lung function in the mouse: the challenge of size. Respir Res. 2003;4:4.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Townsley MI. Structure and composition of pulmonary arteries, capillaries, and veins. Compr Physiol. 2012;2(1):675–709. https://doi.org/10.1002/cphy.c100081.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013;143(6):1590–8. https://doi.org/10.1378/chest.12-2094.

    Article  CAS  PubMed  Google Scholar 

  187. Kim YS, Kokturk N, Kim JY, Lee SW, Lim J, Choi SJ, et al. Gene profiles in a smoke-induced COPD mouse lung model following treatment with mesenchymal stem cells. Mol Cells. 2016;39(10):728–33. https://doi.org/10.14348/molcells.2016.0095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Ikonomou L, Wagner DE, Turner L, Weiss DJ. Translating basic research into safe and effective cell-based treatments for respiratory diseases. Ann Am Thorac Soc. 2019;16(6):657–68. https://doi.org/10.1513/AnnalsATS.201812-890CME.

    Article  PubMed  Google Scholar 

  189. Wagner DE, Turner L, Panoskaltsis-Mortari A, Weiss DJ, Ikonomou L. Co-opting of ClinicalTrials.gov by patient-funded studies. Lancet Respir Med. 2018;6(8):579–81. https://doi.org/10.1016/S2213-2600(18)30242-X.

    Article  PubMed  Google Scholar 

  190. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J. 2006;28(6):1245–57. https://doi.org/10.1183/09031936.00133805.

    Article  CAS  PubMed  Google Scholar 

  191. Teo GS, Ankrum JA, Martinelli R, Boetto SE, Simms K, Sciuto TE, et al. Mesenchymal stem cells transmigrate between and directly through tumor necrosis factor-alpha-activated endothelial cells via both leukocyte-like and novel mechanisms. Stem Cells (Dayton, Ohio). 2012;30(11):2472–86. https://doi.org/10.1002/stem.1198.

    Article  CAS  Google Scholar 

  192. Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med. 2019;7(2):154–62. https://doi.org/10.1016/s2213-2600(18)30418-1.

    Article  PubMed  Google Scholar 

  193. Erickson MA, Liang WS, Fernandez EG, Bullock KM, Thysell JA, Banks WA. Genetics and sex influence peripheral and central innate immune responses and blood-brain barrier integrity. PLoS One. 2018;13(10):e0205769. https://doi.org/10.1371/journal.pone.0205769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Lohan P, Treacy O, Morcos M, Donohoe E, O’Donoghue Y, Ryan AE, et al. Interspecies incompatibilities limit the immunomodulatory effect of human mesenchymal stromal cells in the rat. Stem Cells (Dayton, Ohio). 2018;36(8):1210–5. https://doi.org/10.1002/stem.2840.

    Article  CAS  PubMed  Google Scholar 

  195. Karlsen TA, Brinchmann JE. Expression of inflammatory cytokines in mesenchymal stromal cells is sensitive to culture conditions and simple cell manipulations. Exp Cell Res. 2019;374(1):122–7. https://doi.org/10.1016/j.yexcr.2018.11.014.

    Article  CAS  PubMed  Google Scholar 

  196. De Witte SFH, Peters FS, Merino A, Korevaar SS, Van Meurs JBJ, O’Flynn L, et al. Epigenetic changes in umbilical cord mesenchymal stromal cells upon stimulation and culture expansion. Cytotherapy. 2018;20(7):919–29. https://doi.org/10.1016/j.jcyt.2018.05.005.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The Knut and Alice Wallenberg foundation, the Medical Faculty at Lund University, and Region Skåne are acknowledged for generous financial support (D.E.W).

Author information

Authors and Affiliations

  1. Department of Experimental Medical Sciences, Faculty of Medicine, Lung Bioengineering and Regeneration, Lund University, Lund, Sweden

    Deniz A. Bölükbas, Iran Augusto Neves Da Silva, Kristina Rydell-Törmänen & Darcy E. Wagner

  2. Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Lund University, Lund University, Lund, Sweden

    Deniz A. Bölükbas, Iran Augusto Neves Da Silva, Kristina Rydell-Törmänen & Darcy E. Wagner

  3. Lund Stem Cell Center, Lund University, Lund, Sweden

    Deniz A. Bölükbas, Iran Augusto Neves Da Silva, Kristina Rydell-Törmänen & Darcy E. Wagner

Authors
  1. Deniz A. Bölükbas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iran Augusto Neves Da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristina Rydell-Törmänen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Darcy E. Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Darcy E. Wagner .

Editor information

Editors and Affiliations

  1. The University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands

    Janette K. Burgess

  2. The University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands

    Irene H. Heijink

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Bölükbas, D.A., Da Silva, I.A.N., Rydell-Törmänen, K., Wagner, D.E. (2019). Preclinical Evidence for the Role of Stem/Stromal Cells in COPD. In: Burgess, J., Heijink, I. (eds) Stem Cell-Based Therapy for Lung Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-29403-8_5

Download citation

Publish with us

Policies and ethics

Search

Navigation