Dynamic Reciprocity: The Role of the Extracellular Matrix Microenvironment in Amplifying and Sustaining Pathological Lung Fibrosis

  • Janette K. BurgessEmail author
  • Kirsten Muizer
  • Corry-Anke Brandsma
  • Irene H. Heijink
Part of the Molecular and Translational Medicine book series (MOLEMED)


When taken together fibrotic lung diseases are the leading cause of mortality worldwide, but our understanding of the underlying mechanisms driving these processes is limited. The lung consists of defined parts including the airways and parenchyma. The principal building blocks of these parts are the extracellular matrix (ECM). The ECM supports cells structurally while also acting as a bioactive environment directing cellular responses during pathological events in the lung. Airway and parenchymal tissue ECM alterations characterize the changes identified in many fibrotic lung diseases, including in asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Characterization of the profiles of changes and investigation into how these ECM changes contribute to the disease process has been the recent focus within the field. Studies suggest that the changes in the composition, organization, and stiffness of the ECM environment in the lung may drive functional responses of cells and thereby contribute to the pathological outcome. This chapter aims to summarize the state of the art regarding the dynamic interchange of the ECM in pulmonary fibrotic diseases and the approaches for modulating these aberrations in the future. The overarching goal is to expand knowledge of the contributions of the ECM to enable a better understanding of fibrotic lung diseases and to identify novel approaches for therapeutic targeting in this area.


Asthma Chronic obstructive pulmonary disease (COPD) Idiopathic pulmonary fibrosis (IPF) Fibrosis Extracellular matrix 



Adipose-derived MSCs


Airway smooth muscle


Alveolar type I cells


Alveolar type II cells


Bronchoalveolar lavage


Basement membrane


Bone marrow-derived MSCs


Bronchiolitis obliterans syndrome


Chronic obstructive pulmonary disease


Damage-associated molecular patterns


Extracellular matrix


Epithelial-to-mesenchymal transition


Endoplasmic reticulum


Fibroblast growth factor


Hepatocyte growth factor


Heparin sulfate proteoglycan


Insulin-like growth factor


Idiopathic pulmonary disease


Matrix metalloproteinases


Mesenchymal stromal/stem cells


Platelet-derived growth factor




Prostaglandin E2


Pro-surfactant protein C


Transforming growth factor


Umbilical cord-derived MSCs


Vascular endothelial growth factor




Yes-associated protein


Alpha-smooth muscle actin


  1. 1.
    Rosmark O, Ahrman E, Muller C, Elowsson Rendin L, Eriksson L, Malmstrom A, et al. Quantifying extracellular matrix turnover in human lung scaffold cultures. Sci Rep. 2018;8(1):5409.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Jarvelainen H, Sainio A, Koulu M, Wight TN, Penttinen R. Extracellular matrix molecules: potential targets in pharmacotherapy. Pharmacol Rev. 2009;61(2):198–223.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Burgstaller G, Oehrle B, Gerckens M, et al. The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease. Eur Respir J 2017;50:1601805. Scholar
  4. 4.
    Huxley-Jones J, Foord SM, Barnes MR. Drug discovery in the extracellular matrix. Drug Discov Today. 2008;13(15–16):685–94.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010;123(Pt 24):4195–200.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Balestrini JL, Chaudhry S, Sarrazy V, Koehler A, Hinz B. The mechanical memory of lung myofibroblasts. Integr Biol: Quant Biosci Nano Macro. 2012;4(4):410–21.CrossRefGoogle Scholar
  7. 7.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    White ES. Lung extracellular matrix and fibroblast function. Ann Am Thorac Soc. 2015;12(Suppl 1):S30–3.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Pelosi P, Rocco PR, Negrini D, Passi A. The extracellular matrix of the lung and its role in edema formation. An Acad Bras Cienc. 2007;79(2):285–97.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Kulkarni T, O'Reilly P, Antony VB, Gaggar A, Thannickal VJ. Matrix remodeling in pulmonary fibrosis and emphysema. Am J Respir Cell Mol Biol. 2016;54(6):751–60.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Burgess JK. The role of the extracellular matrix and specific growth factors in the regulation of inflammation and remodelling in asthma. Pharmacol Ther. 2009;122(1):19–29.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Burgess JK, Weckmann M. Matrikines and the lungs. Pharmacol Ther. 2012;134:317–37.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Kristensen JH, Karsdal MA, Genovese F, Johnson S, Svensson B, Jacobsen S, et al. The role of extracellular matrix quality in pulmonary fibrosis. Respiration. 2014;88(6):487–99.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Kruegel J, Miosge N. Basement membrane components are key players in specialized extracellular matrices. Cell Mol Life Sci. 2010;67(17):2879–95.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol. 2003;4(2):140–56.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 2004;20(1):33–43.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Balestrini JL, Gard AL, Gerhold KA, Wilcox EC, Liu A, Schwan J, et al. Comparative biology of decellularized lung matrix: implications of species mismatch in regenerative medicine. Biomaterials. 2016;102:220–30.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Dunsmore SE, Rannels DE. Extracellular matrix biology in the lung. Am J Phys. 1996;270(1 Pt 1):L3–27.Google Scholar
  19. 19.
    Karsdal MA, Nielsen SH, Leeming DJ, Langholm LL, Nielsen MJ, Manon-Jensen T, et al. The good and the bad collagens of fibrosis – their role in signaling and organ function. Adv Drug Deliv Rev. 2017;121:43–56.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Kadler KE, Baldock C, Bella J, Boot-Handford RP. Collagens at a glance. J Cell Sci. 2007;120(Pt 12):1955–8.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Smith ML, Gourdon D, Little WC, Kubow KE, Eguiluz RA, Luna-Morris S, et al. Force-induced unfolding of fibronectin in the extracellular matrix of living cells. PLoS Biol. 2007;5(10):e268.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Souza-Fernandes AB, Pelosi P, Rocco PR. Bench-to-bedside review: the role of glycosaminoglycans in respiratory disease. Crit Care. 2006;10(6):237.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Kadler KE, Hill A, Canty-Laird EG. Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators. Curr Opin Cell Biol. 2008;20(5):495–501.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Kolb M, Margetts PJ, Sime PJ, Gauldie J. Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J Phys Lung Cell Mol Phys. 2001;280(6):L1327–34.Google Scholar
  25. 25.
    Jones FS, Jones PL. The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling. Dev Dyn. 2000;218(2):235–59.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Trebaul A, Chan EK, Midwood KS. Regulation of fibroblast migration by tenascin-C. Biochem Soc Trans. 2007;35(Pt 4):695–7.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Giblin SP, Midwood KS. Tenascin-C: form versus function. Cell Adhes Migr. 2015;9(1–2):48–82.CrossRefGoogle Scholar
  28. 28.
    Mott JD, Werb Z. Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol. 2004;16(5):558–64.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Huber HL, Koessler KK. The pathology of bronchial asthma. Arch Intern Med. 1922;30:689–760.CrossRefGoogle Scholar
  30. 30.
    Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet. 1989;1(8637):520–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Payne DN, Rogers AV, Adelroth E, Bandi V, Guntupalli KK, Bush A, et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med. 2003;167(1):78–82.PubMedCrossRefGoogle Scholar
  32. 32.
    Broekema M, Timens W, Vonk JM, Volbeda F, Lodewijk ME, Hylkema MN, et al. Persisting remodeling and less airway wall eosinophil activation in complete remission of asthma. Am J Respir Crit Care Med. 2011;183(3):310–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Mauad T, Bel EH, Sterk PJ. Asthma therapy and airway remodeling. J Allergy Clin Immunol. 2007;120(5):997–1009; quiz 1010–1.PubMedCrossRefGoogle Scholar
  34. 34.
    Araujo BB, Dolhnikoff M, Silva LFF, Elliot J, Lindeman JHN, Ferreira DS, et al. Extracellular matrix components and regulators in the airway smooth muscle in asthma. Eur Respir J. 2008;32(1):61–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Mauad T, Ferreira DS, Costa MB, Araujo BB, Silva LF, Martins MA, et al. Characterization of autopsy-proven fatal asthma patients in Sao Paulo, Brazil. Rev Panam Salud Publica. 2008;23(6):418–23.PubMedCrossRefGoogle Scholar
  36. 36.
    de Medeiros Matsushita M, da Silva LF, dos Santos MA, Fernezlian S, Schrumpf JA, Roughley P, et al. Airway proteoglycans are differentially altered in fatal asthma. J Pathol. 2005;207(1):102–10.PubMedCrossRefGoogle Scholar
  37. 37.
    Benayoun L, Druilhe A, Dombret M-C, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med. 2003;167(10):1360–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Chakir J, Shannon J, Molet S, Fukakusa M, Elias J, Laviolette M, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol. 2003;111(6):1293–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Weitoft M, Andersson C, Andersson-Sjoland A, Tufvesson E, Bjermer L, Erjefalt J, et al. Controlled and uncontrolled asthma display distinct alveolar tissue matrix compositions. Respir Res. 2014;15:67.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol. 2009;4:435–59.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Abboud RT, Vimalanathan S. Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema. Int J Tuberc Lung Dis. 2008;12(4):361–7.PubMedPubMedCentralGoogle Scholar
  42. 42.
    MacNee W. Pathogenesis of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(4):258–66; discussion 290–1.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Merrilees MJ, Ching PS, Beaumont B, Hinek A, Wight TN, Black PN. Changes in elastin, elastin binding protein and versican in alveoli in chronic obstructive pulmonary disease. Respir Res. 2008;9:41.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Deslee G, Woods JC, Moore CM, Liu L, Conradi SH, Milne M, et al. Elastin expression in very severe human COPD. Eur Respir J. 2009;34(2):324–31.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Salazar LM, Herrera AM. Fibrotic response of tissue remodeling in COPD. Lung. 2011;189(2):101–9.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Oudijk EJ, Lammers JW, Koenderman L. Systemic inflammation in chronic obstructive pulmonary disease. Eur Respir J Suppl. 2003;46:5s–13s.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Black PN, Ching PS, 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.PubMedCrossRefGoogle Scholar
  48. 48.
    Annoni R, Lancas T, Tanigawa RY, de Medeiros Matsushita M, de Morais Fernezlian S, Bruno A, et al. Extracellular matrix composition in chronic obstructive pulmonary disease. Eur Respir J. 2012;40(6):1362–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Fukuda Y, Masuda Y, Ishizaki M, Masugi Y, Ferrans VJ. Morphogenesis of abnormal elastic fibers in lungs of patients with panacinar and centriacinar emphysema. Hum Pathol. 1989;20(7):652–9.PubMedCrossRefGoogle Scholar
  50. 50.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Eurlings IM, Dentener MA, Cleutjens JP, Peutz CJ, Rohde GG, Wouters EF, et al. Similar matrix alterations in alveolar and small airway walls of COPD patients. BMC Pulm Med. 2014;14:90.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Harju T, Kinnula VL, Paakko P, Salmenkivi K, Risteli J, Kaarteenaho R. Variability in the precursor proteins of collagen I and III in different stages of COPD. Respir Res. 2010;11:165.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Pini L, Pinelli V, Modina D, Bezzi M, Tiberio L, Tantucci C. Central airways remodeling in COPD patients. Int J Chron Obstruct Pulmon Dis. 2014;9:927–32.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kranenburg AR, Willems-Widyastuti A, Moori WJ, Sterk PJ, Alagappan VK, de Boer WI, et al. Enhanced bronchial expression of extracellular matrix proteins in chronic obstructive pulmonary disease. Am J Clin Pathol. 2006;126(5):725–35.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Tjin G, Xu P, Kable SH, Kable EP, Burgess JK. Quantification of collagen I in airway tissues using second harmonic generation. J Biomed Opt. 2014;19(3):36005.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Abraham T, Hogg J. Extracellular matrix remodeling of lung alveolar walls in three dimensional space identified using second harmonic generation and multiphoton excitation fluorescence. J Struct Biol. 2010;171(2):189–96.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    van Straaten JF, Coers W, Noordhoek JA, Huitema S, Flipsen JT, Kauffman HF, et al. Proteoglycan changes in the extracellular matrix of lung tissue from patients with pulmonary emphysema. Mod Pathol. 1999;12(7):697–705.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Zandvoort A, Postma DS, Jonker MR, Noordhoek JA, Vos JT, van der Geld YM, et al. Altered expression of the Smad signalling pathway: implications for COPD pathogenesis. Eur Respir J. 2006;28(3):533–41.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Hallgren O, Nihlberg K, Dahlback M, Bjermer L, Eriksson LT, Erjefalt JS, et al. Altered fibroblast proteoglycan production in COPD. Respir Res. 2010;11:55.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Liesker JJ, Ten Hacken NH, Zeinstra-Smith M, Rutgers SR, Postma DS, Timens W. Reticular basement membrane in asthma and COPD: similar thickness, yet different composition. Int J Chron Obstruct Pulmon Dis. 2009;4:127–35.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Kuhn C 3rd, Boldt J, King TE Jr, Crouch E, Vartio T, McDonald JA. An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis. 1989;140(6):1693–703.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Kage H, Borok Z. EMT and interstitial lung disease: a mysterious relationship. Curr Opin Pulm Med. 2012;18(5):517–23.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Bensadoun ES, Burke AK, Hogg JC, Roberts CR. Proteoglycan deposition in pulmonary fibrosis. Am J Respir Crit Care Med. 1996;154(6 Pt 1):1819–28.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Estany S, Vicens-Zygmunt V, Llatjos R, Montes A, Penin R, Escobar I, et al. Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFbeta1. BMC Pulm Med. 2014;14:120.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Enomoto N, Suda T, Kono M, Kaida Y, Hashimoto D, Fujisawa T, et al. Amount of elastic fibers predicts prognosis of idiopathic pulmonary fibrosis. Respir Med. 2013;107(10):1608–16.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Parker MW, Rossi D, Peterson M, Smith K, Sikstrom K, White ES, et al. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest. 2014;124(4):1622–35.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Gattazzo F, Urciuolo A, Bonaldo P. Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim Biophys Acta. 2014;1840(8):2506–19.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Hynes RO, Naba A. Overview of the matrisome – an inventory of extracellular matrix constituents and functions. Cold Spring Harb Perspect Biol. 2012;4(1):a004903.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Gaggar A, Weathington N. Bioactive extracellular matrix fragments in lung health and disease. J Clin Invest. 2016;126(9):3176–84.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Davis GE, Bayless KJ, Davis MJ, Meininger GA. Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. Am J Pathol. 2000;156(5):1489–98.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Schenk S, Quaranta V. Tales from the crypt[ic] sites of the extracellular matrix. Trends Cell Biol. 2003;13(7):366–75.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Ricard-Blum S, Ballut L. Matricryptins derived from collagens and proteoglycans. Front Biosci. 2011;16:674–97.CrossRefGoogle Scholar
  73. 73.
    Ricard-Blum S, Vallet SD. Fragments generated upon extracellular matrix remodeling: Biologicalregulators and potential drugs, Matrix Biol (2017),
  74. 74.
    Akthar S, Patel DF, Beale RC, Peiro T, Xu X, Gaggar A, et al. Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection. Nat Commun. 2015;6:8423.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Pouwels SD, Heijink IH, ten Hacken NH, Vandenabeele P, Krysko DV, Nawijn MC, et al. DAMPs activating innate and adaptive immune responses in COPD. Mucosal Immunol. 2014;7(2):215–26.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Sun ZQ, Guo SS, Fassler R. Integrin-mediated mechanotransduction. J Cell Biol. 2016;215(4):445–56.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Barczyk M, Carracedo S, Gullberg D. Integrins. Cell Tissue Res. 2010;339(1):269–80.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Roberts CR, Walker DC, Schellenberg RR. Extracellular matrix. Clin Allergy Immunol. 2002;16:143–78.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Tran T, Halayko AJ. Extracellular matrix and airway smooth muscle interactions: a target for modulating airway wall remodelling and hyperresponsiveness? Can J Physiol Pharmacol. 2007;85(7):666–71.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Parameswaran K, Radford K, Zuo J, Janssen LJ, O’Byrne PM, Cox PG. Extracellular matrix regulates human airway smooth muscle cell migration. Eur Respir J. 2004;24(4):545–51.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Chan V, Burgess JK, Ratoff JC, O’Connor BJ, Greenough A, Lee TH, et al. Extracellular matrix regulates enhanced eotaxin expression in asthmatic airway smooth muscle cells. Am J Respir Crit Care Med. 2006;174(4):379–85.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Krimmer DI, Burgess JK, Wooi TK, Black JL, Oliver BG. Matrix proteins from smoke-exposed fibroblasts are pro-proliferative. Am J Respir Cell Mol Biol. 2012;46(1):34–9.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Kutys ML, Doyle AD, Yamada KM. Regulation of cell adhesion and migration by cell-derived matrices. Exp Cell Res. 2013;319(16):2434–9.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Evans MJ, Van Winkle LS, Fanucchi MV, Plopper CG. The attenuated fibroblast sheath of the respiratory tract epithelial-mesenchymal trophic unit. Am J Respir Cell Mol Biol. 1999;21(6):655–7.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Behzad AR, McDonough JE, Seyednejad N, Hogg JC, Walker DC. The disruption of the epithelial mesenchymal trophic unit in COPD. COPD. 2009;6(6):421–31.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Bucchieri F, Pitruzzella A, Fucarino A, Gammazza AM, Bavisotto CC, Marciano V, et al. Functional characterization of a novel 3D model of the epithelial-mesenchymal trophic unit. Exp Lung Res. 2017;43(2):82–92.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, et al. Cell migration: integrating signals from front to back. Science. 2003;302(5651):1704–9.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Lammermann T, Sixt M. Mechanical modes of ‘amoeboid’ cell migration. Curr Opin Cell Biol. 2009;21(5):636–44.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Charras G, Sahai E. Physical influences of the extracellular environment on cell migration. Nat Rev Mol Cell Biol. 2014;15(12):813–24.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Gershlak JR, Black LD 3rd. Beta 1 integrin binding plays a role in the constant traction force generation in response to varying stiffness for cells grown on mature cardiac extracellular matrix. Exp Cell Res. 2015;330(2):311–24.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Tufvesson E, Westergren-Thorsson G. Biglycan and decorin induce morphological and cytoskeletal changes involving signalling by the small GTPases RhoA and Rac1 resulting in lung fibroblast migration. J Cell Sci. 2003;116(Pt 23):4857–64.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Freyer AM, Johnson SR, Hall IP. Effects of growth factors and extracellular matrix on survival of human airway smooth muscle cells. Am J Respir Cell Mol Biol. 2001;25(5):569–76.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Hirst SJ, Twort CH, Lee TH. Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. Am J Respir Cell Mol Biol. 2000;23(3):335–44.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Hirst SJ, Walker TR, Chilvers ER. Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma. Eur Respir J. 2000;16(1):159–77.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Andersson-Sjoland A, Hallgren O, Rolandsson S, Weitoft M, Tykesson E, Larsson-Callerfelt AK, et al. Versican in inflammation and tissue remodeling: the impact on lung disorders. Glycobiology. 2015;25(3):243–51.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Zimmermann DR, Dours-Zimmermann MT, Schubert M, Bruckner-Tuderman L. Versican is expressed in the proliferating zone in the epidermis and in association with the elastic network of the dermis. J Cell Biol. 1994;124(5):817–25.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Tufvesson E, Westergren-Thorsson G. Tumour necrosis factor-alpha interacts with biglycan and decorin. FEBS Lett. 2002;530(1–3):124–8.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Westergren-Thorsson G, Onnervik PO, Fransson LA, Malmstrom A. Proliferation of cultured fibroblasts is inhibited by L-iduronate-containing glycosaminoglycans. J Cell Physiol. 1991;147(3):523–30.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Westergren-Thorsson G, Persson S, Isaksson A, Onnervik PO, Malmstrom A, Fransson LA. L-iduronate-rich glycosaminoglycans inhibit growth of normal fibroblasts independently of serum or added growth factors. Exp Cell Res. 1993;206(1):93–9.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Malmstrom J, Westergren-Thorsson G. Heparan sulfate upregulates platelet-derived growth factor receptors on human lung fibroblasts. Glycobiology. 1998;8(12):1149–55.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Plotnikov SV, Waterman CM. Guiding cell migration by tugging. Curr Opin Cell Biol. 2013;5:619–26.CrossRefGoogle Scholar
  102. 102.
    Yuan Y, Zhong W, Ma G, Zhang B, Tian H. Yes-associated protein regulates the growth of human non-small cell lung cancer in response to matrix stiffness. Mol Med Rep. 2015;11:4267–72.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Liu F, Lagares D, Choi KM, Stopfer L, Marinkovic A, Vrbanac V, et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Phys Lung Cell Mol Phys. 2015;308(4):L344–57.Google Scholar
  104. 104.
    Rydell-Tormanen K, Andreasson K, Hesselstrand R, Risteli J, Heinegard D, Saxne T, et al. Extracellular matrix alterations and acute inflammation; developing in parallel during early induction of pulmonary fibrosis. Lab Inv; J Tech Methods Pathol. 2012;92(6):917–25.CrossRefGoogle Scholar
  105. 105.
    Martinez FD. Asthma treatment and asthma prevention: a tale of 2 parallel pathways. J Allergy Clin Immunol. 2007;119(1):30–3.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Grainge CL, Lau LC, Ward JA, Dulay V, Lahiff G, Wilson S, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med. 2011;364(21):2006–15.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Larsen NP, Paddock R, Alexander HL. Historical document, 1922. Bronchial asthma and allied conditions. Clinical and immunological observations. Ann Allergy. 1961;19:771–8.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Burgess JK. The extracellular matrix: friend or foe in airway disease? Minerva Pneumol. 2010;49(4):219–36.Google Scholar
  109. 109.
    Johnson PR, Burgess JK, Underwood PA, Au W, Poniris MH, Tamm M, et al. Extracellular matrix proteins modulate asthmatic airway smooth muscle cell proliferation via an autocrine mechanism. J Allergy Clin Immunol. 2004;113(4):690–6.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Johnson PRA, Roth M, Tamm M, Hughes JM, Ge Q, King G, et al. Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med. 2001;164:474–7.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Lau JY, Oliver BG, Baraket M, Beckett EL, Hansbro NG, Moir LM, et al. Fibulin-1 is increased in asthma – a novel mediator of airway remodeling? PLoS One. 2010;5(10):e13360.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Harkness LM, Weckmann M, Kopp M, Becker T, Ashton AW, Burgess JK. Tumstatin regulates the angiogenic and inflammatory potential of airway smooth muscle extracellular matrix. J Cell Mol Med. 2017;21:3288–97.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Black JL, Burgess JK, Johnson PR. Airway smooth muscle – its relationship to the extracellular matrix. Respir Physiol Neurobiol. 2003;137(2–3):339–46.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Hirst SJ, Martin JG, Bonacci JV, Chan V, Fixman ED, Hamid QA, et al. Proliferative aspects of airway smooth muscle. J Allergy Clin Immunol. 2004;114(2 Suppl):S2–17.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Howarth PH, Knox AJ, Amrani Y, Tliba O, Panettieri RA Jr, Johnson M. Synthetic responses in airway smooth muscle. J Allergy Clin Immunol. 2004;114(2 Suppl):S32–50.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Johnson PR, Black JL, Carlin S, Ge Q, Underwood PA. The production of extracellular matrix proteins by human passively sensitized airway smooth-muscle cells in culture: the effect of beclomethasone. Am J Respir Crit Care Med. 2000;162(6):2145–51.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Johnson PRA, Burgess JK, Ge Q, Poniris M, Boustany S, Twigg SM, et al. Connective tissue growth factor and transforming growth factor β induces extracellular matrix in asthmatic airway smooth muscle. Am J Respir Crit Care Med. 2005;2(abstracts issue):A250.Google Scholar
  118. 118.
    Panettieri RA, Tan EM, Ciocca V, Luttmann MA, Leonard TB, Hay DW. Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol. 1998;19(3):453–61.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Robertson IB, Horiguchi M, Zilberberg L, Dabovic B, Hadjiolova K, Rifkin DB. Latent TGF-beta-binding proteins. Matrix Biol. 2015;47:44–53.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Tatler AL, John AE, Jolly L, Habgood A, Porte J, Brightling C, et al. Integrin alphavbeta5-mediated TGF-beta activation by airway smooth muscle cells in asthma. J Immunol. 2011;187(11):6094–107.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Johnson PR, Burgess JK, Ge Q, Poniris M, Boustany S, Twigg SM, et al. Connective tissue growth factor induces extracellular matrix in asthmatic airway smooth muscle. Am J Respir Crit Care Med. 2006;173(1):32–41.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Xie S, Sukkar MB, Issa R, Khorasani NM, Chung KF. Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta. Am J Phys Lung Cell Mol Phys. 2007;293(1):L245–53.Google Scholar
  123. 123.
    Xie S, Sukkar MB, Issa R, Oltmanns U, Nicholson AG, Chung KF. Regulation of TGF-{beta}1-induced connective tissue growth factor expression in airway smooth muscle cells. Am J Phys Lung Cell Mol Phys. 2005;288:L68–76.Google Scholar
  124. 124.
    Larsen K, Tufvesson E, Malmstrom J, Morgelin M, Wildt M, Andersson A, et al. Presence of activated mobile fibroblasts in bronchoalveolar lavage from patients with mild asthma. Am J Respir Crit Care Med. 2004;170(10):1049–56.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Scheja A, Larsen K, Todorova L, Tufvesson E, Wildt M, Akesson A, et al. BALF-derived fibroblasts differ from biopsy-derived fibroblasts in systemic sclerosis. Eur Respir J. 2007;29(3):446–52.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    McParland BE, Macklem PT, Pare PD. Airway wall remodeling: friend or foe? J Appl Physiol. 2003;95(1):426–34.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Nagai A, West WW, Thurlbeck WM. The National Institutes of Health intermittent positive-pressure breathing trial: pathology studies. II. Correlation between morphologic findings, clinical findings, and evidence of expiratory air-flow obstruction. Am Rev Respir Dis. 1985;132(5):946–53.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Niimi A, Matsumoto H, Takemura M, Ueda T, Chin K, Mishima M. Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma. Am J Respir Crit Care Med. 2003;168(8):983–8.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Zandvoort A, Postma DS, Jonker MR, Noordhoek JA, Vos JT, Timens W. Smad gene expression in pulmonary fibroblasts: indications for defective ECM repair in COPD. Respir Res. 2008;9:83.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Ichimaru Y, Krimmer DI, Burgess JK, Black JL, Oliver BG. TGF-beta enhances deposition of perlecan from COPD airway smooth muscle. Am J Phys Lung Cell Mol Phys. 2012;302(3):L325–33.Google Scholar
  131. 131.
    Osei ET, Noordhoek JA, Hackett TL, Spanjer AI, Postma DS, Timens W, et al. Interleukin-1alpha drives the dysfunctional cross-talk of the airway epithelium and lung fibroblasts in COPD. Eur Respir J. 2016;48(2):359–69.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Westergren-Thorsson G, Sime P, Jordana M, Gauldie J, Sarnstrand B, Malmstrom A. Lung fibroblast clones from normal and fibrotic subjects differ in hyaluronan and decorin production and rate of proliferation. Int J Biochem Cell Biol. 2004;36(8):1573–84.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Andersson-Sjoland A, Thiman L, Nihlberg K, Hallgren O, Rolandsson S, Skog I, et al. Fibroblast phenotypes and their activity are changed in the wound healing process after lung transplantation. J Heart Lung Transplant: Off Publ Int Soc Heart Transplant. 2011;30(8):945–54.Google Scholar
  134. 134.
    Westergren-Thorsson G, Hedstrom U, Nybom A, Tykesson E, Ahrman E, Hornfelt M, et al. Increased deposition of glycosaminoglycans and altered structure of heparan sulfate in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol. 2017;83:27–38.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Fernandez IE, Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet. 2012;380(9842):680–8.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Booth AJ, Hadley R, Cornett AM, Dreffs AA, Matthes SA, Tsui JL, et al. Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation. Am J Respir Crit Care Med. 2012;186(9):866–76.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Reich A, Meurer M, Eckes B, Friedrichs J, Muller DJ. Surface morphology and mechanical properties of fibroblasts from scleroderma patients. J Cell Mol Med. 2009;13(8B):1644–52.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Liu F, Mih JD, Shea BS, Kho AT, Sharif AS, Tager AM, et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J Cell Biol. 2010;190(4):693–706.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Marinkovic A, Liu F, Tschumperlin DJ. Matrices of physiologic stiffness potently inactivate idiopathic pulmonary fibrosis fibroblasts. Am J Respir Cell Mol Biol. 2013;48(4):422–30.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Alvarez D, Levine M, Rojas M. Regenerative medicine in the treatment of idiopathic pulmonary fibrosis: current position. Stem Cells Cloning. 2015;8:61–5.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Chilosi M, Carloni A, Rossi A, Poletti V. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl Res. 2013;162(3):156–73.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Armanios M. Telomerase and idiopathic pulmonary fibrosis. Mutat Res. 2012;730(1–2):52–8.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 2008;105(35):13051–6.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Marmai C, Sutherland RE, Kim KK, Dolganov GM, Fang X, Kim SS, et al. Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis. Am J Phys Lung Cell Mol Phys. 2011;301(1):L71–8.Google Scholar
  145. 145.
    Naikawadi RP, Disayabutr S, Mallavia B, Donne ML, Green G, La JL, et al. Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis. JCI Insight. 2016;1(14):e86704.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Rock JR, Hogan BL. Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu Rev Cell Dev Biol. 2011;27:493–512.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Chapman HA, Li X, Alexander JP, Brumwell A, Lorizio W, Tan K, et al. Integrin alpha6beta4 identifies an adult distal lung epithelial population with regenerative potential in mice. J Clin Invest. 2011;121(7):2855–62.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Li X, Rossen N, Sinn PL, Hornick AL, Steines BR, Karp PH, et al. Integrin alpha6beta4 identifies human distal lung epithelial progenitor cells with potential as a cell-based therapy for cystic fibrosis lung disease. PLoS One. 2013;8(12):e83624.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Rolandsson S, Andersson Sjoland A, Brune JC, Li H, Kassem M, Mertens F, et al. Primary mesenchymal stem cells in human transplanted lungs are CD90/CD105 perivascularly located tissue-resident cells. BMJ Open Respir Res. 2014;1(1):e000027.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Ricciardi M, Malpeli G, Bifari F, Bassi G, Pacelli L, Nwabo Kamdje AH, et al. Comparison of epithelial differentiation and immune regulatory properties of mesenchymal stromal cells derived from human lung and bone marrow. PLoS One. 2012;7(5):e35639.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Ingenito EP, Tsai L, Murthy S, Tyagi S, Mazan M, Hoffman A. Autologous lung-derived mesenchymal stem cell transplantation in experimental emphysema. Cell Transplant. 2012;21(1):175–89.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Lindahl P, Karlsson L, Hellstrom M, Gebre-Medhin S, Willetts K, Heath JK, et al. Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development. Development. 1997;124(20):3943–53.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Toonkel RL, Hare JM, Matthay MA, Glassberg MK. Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am J Respir Crit Care Med. 2013;188(2):133–40.PubMedCrossRefGoogle Scholar
  154. 154.
    Tashiro J, Rubio GA, Limper AH, Williams K, Elliot SJ, Ninou I, et al. Exploring animal models that resemble idiopathic pulmonary fibrosis. Front Med (Lausanne). 2017;4:118.CrossRefGoogle Scholar
  155. 155.
    Srour N, Thebaud B. Mesenchymal stromal cells in animal bleomycin pulmonary fibrosis models: a systematic review. Stem Cells Transl Med. 2015;4(12):1500–10.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. 2003;100(14):8407–11.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, et al. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 2005;33(2):145–52.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, et al. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol. 2009;175(1):303–13.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Cargnoni A, Gibelli L, Tosini A, Signoroni PB, Nassuato C, Arienti D, et al. Transplantation of allogeneic and xenogeneic placenta-derived cells reduces bleomycin-induced lung fibrosis. Cell Transplant. 2009;18(4):405–22.PubMedCrossRefGoogle Scholar
  160. 160.
    Lee SH, Lee EJ, Lee SY, Kim JH, Shim JJ, Shin C, et al. The effect of adipose stem cell therapy on pulmonary fibrosis induced by repetitive intratracheal bleomycin in mice. Exp Lung Res. 2014;40(3):117–25.PubMedCrossRefGoogle Scholar
  161. 161.
    Lee SH, Jang AS, Kim YE, Cha JY, Kim TH, Jung S, et al. Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis. Respir Res. 2010;11:16.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Kumamoto M, Nishiwaki T, Matsuo N, Kimura H, Matsushima K. Minimally cultured bone marrow mesenchymal stem cells ameliorate fibrotic lung injury. Eur Respir J. 2009;34(3):740–8.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Tashiro J, Elliot SJ, Gerth DJ, Xia X, Pereira-Simon S, Choi R, et al. Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis. Transl Res. 2015;166(6):554–67.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Reddy M, Fonseca L, Gowda S, Chougule B, Hari A, Totey S. Human adipose-derived mesenchymal stem cells attenuate early stage of bleomycin induced pulmonary fibrosis: comparison with pirfenidone. Int J Stem Cells. 2016;9(2):192–206.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Mora AL, Rojas M. Adult stem cells for chronic lung diseases. Respirology. 2013;18(7):1041–6.PubMedPubMedCentralGoogle Scholar
  166. 166.
    Jiang X, Jiang X, Qu C, Chang P, Zhang C, Qu Y, et al. Intravenous delivery of adipose-derived mesenchymal stromal cells attenuates acute radiation-induced lung injury in rats. Cytotherapy. 2015;17(5):560–70.PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Li X, Wang Y, An G, Liang D, Zhu Z, Lian X, et al. Bone marrow mesenchymal stem cells attenuate silica-induced pulmonary fibrosis via paracrine mechanisms. Toxicol Lett. 2017;270:96–107.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Royce SG, Shen M, Patel KP, Huuskes BM, Ricardo SD, Samuel CS. Mesenchymal stem cells and serelaxin synergistically abrogate established airway fibrosis in an experimental model of chronic allergic airways disease. Stem Cell Res. 2015;15(3):495–505.PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Wang D, Morales JE, Calame DG, Alcorn JL, Wetsel RA. Transplantation of human embryonic stem cell-derived alveolar epithelial type II cells abrogates acute lung injury in mice. Mol Ther. 2010;18(3):625–34.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Zhou Y, He Z, Gao Y, Zheng R, Zhang X, Zhao L, et al. Induced pluripotent stem cells inhibit bleomycin-induced pulmonary fibrosis in mice through suppressing TGF-beta1/Smad-mediated epithelial to mesenchymal transition. Front Pharmacol. 2016;7:430.PubMedPubMedCentralGoogle Scholar
  172. 172.
    Zhou Q, Ye X, Sun R, Matsumoto Y, Moriyama M, Asano Y, et al. Differentiation of mouse induced pluripotent stem cells into alveolar epithelial cells in vitro for use in vivo. Stem Cells Transl Med. 2014;3(6):675–85.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Serrano-Mollar A, Nacher M, Gay-Jordi G, Closa D, Xaubet A, Bulbena O. Intratracheal transplantation of alveolar type II cells reverses bleomycin-induced lung fibrosis. Am J Respir Crit Care Med. 2007;176(12):1261–8.PubMedCrossRefGoogle Scholar
  174. 174.
    Bustos ML, Huleihel L, Kapetanaki MG, Lino-Cardenas CL, Mroz L, Ellis BM, et al. Aging mesenchymal stem cells fail to protect because of impaired migration and antiinflammatory response. Am J Respir Crit Care Med. 2014;189(7):787–98.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Paxson JA, Gruntman AM, Davis AM, Parkin CM, Ingenito EP, Hoffman AM. Age dependence of lung mesenchymal stromal cell dynamics following pneumonectomy. Stem Cells Dev. 2013;22(24):3214–25.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Mirsaidi A, Kleinhans KN, Rimann M, Tiaden AN, Stauber M, Rudolph KL, et al. Telomere length, telomerase activity and osteogenic differentiation are maintained in adipose-derived stromal cells from senile osteoporotic SAMP6 mice. J Tissue Eng Regen Med. 2012;6(5):378–90.PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Gazdhar A, Grad I, Tamo L, Gugger M, Feki A, Geiser T. The secretome of induced pluripotent stem cells reduces lung fibrosis in part by hepatocyte growth factor. Stem Cell Res Ther. 2014;5(6):123.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Rolandsson S, Karlsson JC, Scheding S, Westergren-Thorsson G. Specific subsets of mesenchymal stroma cells to treat lung disorders – finding the Holy Grail. Pulm Pharmacol Ther. 2014;29:93–5.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Tzouvelekis A, Bouros D. Steep barriers to overcome for successful application of stem cell treatment in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2013;188(2):251–2.PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Glassberg MK, Minkiewicz J, Toonkel RL, Simonet ES, Rubio GA, DiFede D, et al. Allogeneic human mesenchymal stem cells in patients with idiopathic pulmonary fibrosis via intravenous delivery (AETHER): a phase I safety clinical trial. Chest. 2017;151(5):971–81.PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Tzouvelekis A, Ntolios P, Bouros D. Stem cell treatment for chronic lung diseases. Respiration. 2013;85(3):179–92.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Zhang C, Yin X, Zhang J, Ao Q, Gu Y, Liu Y. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe idiopathic pulmonary fibrosis: a case report. Exp Ther Med. 2017;13(5):1922–6.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Chambers DC, Enever D, Ilic N, Sparks L, Whitelaw K, Ayres J, et al. A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology. 2014;19(7):1013–8.PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–82.PubMedCrossRefGoogle Scholar
  185. 185.
    King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083–92.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Janette K. Burgess
    • 1
    Email author
  • Kirsten Muizer
    • 1
  • Corry-Anke Brandsma
    • 1
  • Irene H. Heijink
    • 1
  1. 1.University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC (Groningen Research Institute for Asthma and COPD)GroningenThe Netherlands

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