Skip to main content
SpringerLink
Log in

Growth Factor Signaling in the Maintenance of Adult Lung Homeostasis

  • Chapter
  • First Online:
Tissue-Specific Cell Signaling

  • 592 Accesses

Abstract

The lung needs to maintain its integrity and functionality throughout lifespan since it is critical for survival. At steady-state, lung cell turnover is typically very low, and resident progenitor cells are in a quiescent state. The activation or inhibition of different signaling pathways in epithelial and/or mesenchymal cells of the adult lung tissue is crucial to maintaining the quiescence of progenitor’s niches. Interestingly, growth factors that have been reported as essential for lung development are also key to preserve adult tissue. With this chapter, we aim to describe the current knowledge regarding the molecular players that contribute to maintaining the homeostasis of the adult lung, specifically, SHH, FGF, WNT, Retinoic Acid, TGFβ, BMP, VEGF, and PDGF.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 129.99
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

Similar content being viewed by others

Abbreviations

ABCA3:

ATP Binding Cassette Subfamily A Member 3

AEC:

Alveolar epithelial cells

AM:

Alveolar macrophages

ASMC:

Airway smooth muscle cells

BC:

Basal cells

BMP:

Bone Morphogenetic Protein

CYP26A1:

Cytochrome P450 26A1

DHH:

Desert Hedgehog

FGF:

Fibroblast Growth Factor

FGFR:

Fibroblast Growth Factor Receptor

GLI:

Glioma-associated oncogene

GREM2:

Gremlin 2

IHH:

Indian Hedgehog

LIF:

Lipofibroblast

LRP:

Lipoprotein receptor-related protein

NRP:

Neuropilin

PDGF:

Platelet Derived Growth Factor

PDGFR:

Platelet Derived Growth Factor Receptor

PTCH:

Patched

RA:

Retinoic Acid

RALDH1:

Retinaldehyde dehydrogenase 1

RAR:

Retinoic Acid Receptor

SFRP1:

Secreted frizzled-related protein 1

SHH:

Sonic Hedgehog

SMO:

Smoothened

SOX2:

SRY (sex determining region Y)-box 2

SP:

Surfactant protein

SPRY2:

Sprouty homolog 2

TGFβ:

Transforming Growth Factor β

VEGF:

Vascular Endothelial Growth Factor

VEGFR:

Vascular Endothelial Growth Factor Receptor

WNT:

Wingless-related Integration Site

References

  1. Das S, Stewart P (2016) The influence of lung surfactant liquid crystalline nanostructures on respiratory drug delivery. Int J Pharm 514(2):465–474

    CAS  PubMed  Google Scholar 

  2. Patwa A, Shah A (2015) Anatomy and physiology of respiratory system relevant to anaesthesia. Indian J Anaesth 59(9):533–541

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Suki B, Stamenović D (2011) Lung Parenchymal Mechanics. Compr Physiol 1(3):1317–1351

    PubMed  Google Scholar 

  4. Morrisey E, Hogan B (2010) Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell 18(1):8–23

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Tomashefski JF, Farver CF (2008) Anatomy and histology of the lung. In: Tomashefski JF, Cagle PT, Farver CF, Fraire AE (eds) Dail and Hammar’s pulmonary pathology. Springer, New York, NY, pp 20–48

    Google Scholar 

  6. Herriges M, Morrisey E (2014) Lung development: orchestrating the generation and regeneration of a complex organ. Development 141(3):502–513

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mullassery D, Smith N (2015) Lung development. Semin Pediatr Surg 24(4):152–155

    PubMed  Google Scholar 

  8. Ma J, Rubin B, Voynow J (2018) Mucins, mucus, and goblet cells. Chest 154(1):169–176

    PubMed  Google Scholar 

  9. Evans MJ, Van Winkle LS, Fanucchi MV et al (2001) Cellular and molecular characteristics of basal cells in airway epithelium. Exp Lung Res 27(5):401–415

    CAS  PubMed  Google Scholar 

  10. Cutz E (2015) Hyperplasia of pulmonary neuroendocrine cells in infancy and childhood. Semin Diagn Pathol 32(6):420–437

    PubMed  Google Scholar 

  11. Sonar S, Ehmke M, Marsh L et al (2011) Clara cells drive eosinophil accumulation in allergic asthma. Eur Respir J 39(2):429–438

    PubMed  Google Scholar 

  12. Yang J, Hernandez B, Martinez Alanis D et al (2015) The development and plasticity of alveolar type 1 cells. Development 143(1):54–65

    PubMed  Google Scholar 

  13. Hussell T, Bell T (2014) Alveolar macrophages: plasticity in a tissue-specific context. Nat Rev Immunol 14(2):81–93

    CAS  PubMed  Google Scholar 

  14. Petrova R, Joyner A (2014) Roles for Hedgehog signaling in adult organ homeostasis and repair. Development 141(18):3445–3457

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee R, Zhao Z, Ingham P (2016) Hedgehog signalling. Development 143(3):367–372

    CAS  PubMed  Google Scholar 

  16. Fernandes-Silva H, Correia-Pinto J, Moura RS (2017) Canonical sonic hedgehog signaling in early lung development. J Dev Biol 5(1):3

    PubMed  PubMed Central  Google Scholar 

  17. Peng T, Frank D, Kadzik R et al (2015) Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration. Nature 526(7574):578–582

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu L, Kugler M, Loomis C et al (2013) Hedgehog signaling in neonatal and adult lung. Am J Respir Cell Mol Biol 48(6):703–710

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Krause A, Xu Y, Joh J et al (2010) Overexpression of sonic hedgehog in the lung mimics the effect of lung injury and compensatory lung growth on pulmonary Sca-1 and CD34 positive cells. Mol Ther 18(2):404–412

    CAS  PubMed  Google Scholar 

  20. Ornitz D, Itoh N (2015) The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol 4(3):215–266

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Fon Tacer K, Bookout A, Ding X et al (2010) Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 24(10):2050–2064

    PubMed  PubMed Central  Google Scholar 

  22. Zepp J, Zacharias W, Frank D et al (2017) Distinct mesenchymal lineages and niches promote epithelial self-renewal and myofibrogenesis in the lung. Cell 170(6):1134–1148

    CAS  PubMed  PubMed Central  Google Scholar 

  23. El Agha E, Herold S, Alam D et al (2014) Fgf10-positive cells represent a progenitor cell population during lung development and postnatally. Development 141(2):296–306

    PubMed  PubMed Central  Google Scholar 

  24. McQualter J, McCarty R, Van der Velden J et al (2013) TGF-β signaling in stromal cells acts upstream of FGF-10 to regulate epithelial stem cell growth in the adult lung. Stem Cell Res 11(3):1222–1233

    CAS  PubMed  Google Scholar 

  25. Volckaert T, Yuan T, Chao C et al (2017) Fgf10-hippo epithelial-mesenchymal crosstalk maintains and recruits lung basal stem cells. Dev Cell 43(1):48–59

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Balasooriya G, Johnson J, Basson M et al (2016) An FGFR1-SPRY2 signaling axis limits basal cell proliferation in the steady-state airway epithelium. Dev Cell 37(1):85–97

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Balasooriya G, Goschorska M, Piddini E et al (2017) FGFR2 is required for airway basal cell self-renewal and terminal differentiation. Development 144(9):1600–1606

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gammons M, Bienz M (2018) Multiprotein complexes governing Wnt signal transduction. Curr Opin Cell Biol 51:42–49

    CAS  PubMed  Google Scholar 

  29. Königshoff M, Eickelberg O (2010) WNT signaling in lung disease. Am J Respir Cell Mol Biol 42(1):21–31

    PubMed  Google Scholar 

  30. Mucenski M, Nation J, Thitoff A, Besnard et al (2005) β-Catenin regulates differentiation of respiratory epithelial cells in vivo. Am J Physiol Lung Cell Mol Physiol 289(6):L971–L979

    Google Scholar 

  31. Reynolds S, Zemke A, Giangreco A et al (2008) Conditional stabilization of β-Catenin expands the pool of lung stem cells. Stem Cells 26(5):1337–1346

    CAS  PubMed  Google Scholar 

  32. Nabhan A, Brownfield D, Harbury P et al (2018) Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science 359(6380):1118–1123

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zacharias W, Frank D, Zepp J et al (2018) Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 555(7695):251–255

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kedishvili N (2016) Retinoic acid synthesis and degradation. Subcell Biochem 81:127–161

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Schünemann HJ, Grant BJ, Freudenheim JL et al (2001) The relation of serum levels of antioxidant Vitamins C and E, retinol and carotenoids with pulmonary function in the general population. Am J Respir Crit Care Med 163(5):1246–1255

    PubMed  Google Scholar 

  36. Collins S, Lucas J, Inskip H et al (2013) HHIP, HDAC4, NCR3 and RARB polymorphisms affect fetal, childhood and adult lung function. Eur Respir J 41(3):756–757

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Ng-Blichfeldt J, Alçada J, Montero M et al (2017) Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema. Thorax 72(6):510–521

    PubMed  Google Scholar 

  38. Ng-Blichfeldt J, Schrik A, Kortekaas R et al (2018) Retinoic acid signaling balances adult distal lung epithelial progenitor cell growth and differentiation. EBioMedicine 36:461–474

    PubMed  PubMed Central  Google Scholar 

  39. Chen F, Shao F, Hinds A et al (2018) Retinoic acid signaling is essential for airway smooth muscle homeostasis. JCI Insight 3(16):e120398

    PubMed  PubMed Central  Google Scholar 

  40. Derynck R, Budi E (2019) Specificity, versatility, and control of TGF-β family signaling. Sci Signal 12(570):eaav5183

    Google Scholar 

  41. Magnan A, Frachon I, Rain B et al (1994) Transforming growth factor beta in normal human lung: preferential location in bronchial epithelial cells. Thorax 49(8):789–792

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Coker R, Laurent G, Shahzeidi S et al (1996) Diverse cellular TGF-beta 1 and TGF-beta 3 gene expression in normal human and murine lung. Eur Respir J 9(12):2501–2507

    CAS  PubMed  Google Scholar 

  43. Ryan R, Mineo-Kuhn M, Kramer C et al (1994) Growth factors alter neonatal type II alveolar epithelial cell proliferation. Am J Physiol Lung Cell Mol Physiol 266(1):L17–L22

    CAS  Google Scholar 

  44. Zhao L, Yee M, O’Reilly M (2013) Transdifferentiation of alveolar epithelial type II to type I cells is controlled by opposing TGF-β and BMP signaling. Am J Physiol Lung Cell Mol Physiol 305(6):L409–L418

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Correll K, Edeen K, Zemans R et al (2018) TGF beta inhibits expression of SP-A, SP-B, SP-C, but not SP-D in human alveolar type II cells. Biochem Biophys Res Commun 499(4):843–848

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lynn T, Molloy E, Masterson J et al (2016) SMAD signaling in the airways of healthy rhesus macaques versus rhesus macaques with asthma highlights a relationship between inflammation and bone morphogenetic proteins. Am J Respir Cell Mol Biol 54(4):562–573

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Tadokoro T, Gao X, Hong C et al (2016) BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors. Development 143(5):764–773

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Chung M, Bujnis M, Barkauskas C et al (2018) Niche-mediated BMP/SMAD signaling regulates lung alveolar stem cell proliferation and differentiation. Development 145(9):dev163014

    Google Scholar 

  49. Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2(7):a006502

    PubMed  PubMed Central  Google Scholar 

  50. Kaner R, Crystal R (2001) Compartmentalization of vascular endothelial growth factor to the epithelial surface of the human lung. Mol Med 7(4):240–246

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Fehrenbach H, Haase M, Kasper M et al (1999) Alterations in the immunohistochemical distribution patterns of vascular endothelial growth factor receptors Flk1 and Flt1 in bleomycin-induced rat lung fibrosis. Virchows Arch 435(1):20–31

    CAS  PubMed  Google Scholar 

  52. Kasahara Y, Tuder R, Taraseviciene-Stewart L et al (2000) Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 106(11):1311–1319

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Roberts J, Perkins G, Fujisawa T et al (2007) Vascular endothelial growth factor promotes physical wound repair and is anti-apoptotic in primary distal lung epithelial and A549 cells. Crit Care Med 35(9):2164–2170

    CAS  PubMed  Google Scholar 

  54. Kearns M, Dalal S, Horstmann S et al (2012) Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells. Am J Physiol Lung Cell Mol Physiol 302(7):L711–L718

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kazlauskas A (2017) PDGFs and their receptors. Gene 614:1–7

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Barkauskas C, Cronce M, Rackley C et al (2013) Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 123(7):3025–3036

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work has been funded by FEDER through the Competitiveness Factors Operational Programme (COMPETE), by National funds through the Foundation for Science and Technology (FCT) under the scope of the project UID/Multi/50026/2019; and by the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER).

Author information

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal

    Henrique Araújo-Silva, Jorge Correia-Pinto & Rute S. Moura

  2. ICVS/3B’s - PT Government Associate Laboratory, University of Minho, 4710-057, Braga/Guimarães, Portugal

    Henrique Araújo-Silva, Jorge Correia-Pinto & Rute S. Moura

  3. Department of Pediatric Surgery, Hospital de Braga, 4710-243, Braga, Portugal

    Jorge Correia-Pinto

Authors
  1. Henrique Araújo-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jorge Correia-Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rute S. Moura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rute S. Moura .

Editor information

Editors and Affiliations

  1. Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine—iBiMED, University of Aveiro, Aveiro, Portugal

    Joana Vieira Silva

  2. Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, Belgium

    Maria João Freitas

  3. Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine—iBiMED, University of Aveiro, Aveiro, Portugal

    Margarida Fardilha

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Araújo-Silva, H., Correia-Pinto, J., Moura, R.S. (2020). Growth Factor Signaling in the Maintenance of Adult Lung Homeostasis. In: Silva, J.V., Freitas, M.J., Fardilha, M. (eds) Tissue-Specific Cell Signaling. Springer, Cham. https://doi.org/10.1007/978-3-030-44436-5_13

Download citation

Publish with us

Policies and ethics

Search

Navigation