Skip to main content
SpringerLink
Log in

The Role of Endothelin-1 in the Pathogenesis of Idiopathic Pulmonary Fibrosis

  • Review Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

The endothelin system participates in a number of critical biologic pathways, including normal wound healing. In addition, emerging basic science, and animal and human data all suggest that endothelin-1 (EDN1, also known as ET-1) is a potentially important contributor in the pathobiology of fibrosing disorders, including those that affect the lung. For example, EDN1 drives fibroblast activation, proliferation, as well as differentiation into myofibroblasts — processes that lead to excessive collagen deposition. Patients with idiopathic pulmonary fibrosis (IPF) have increased levels of EDN1 in both their bronchoalveolar lavage fluid and lung tissue. Beyond this, rodent models suggest that endothelin receptor antagonists can limit bleomycin-induced lung fibrosis. This suggests a biologic rationale for the blockade of EDN1 to limit the evolution of lung fibrosis in humans. Initial results from a trial examining the efficacy of a dual endothelin receptor antagonist suggest that this approach may delay disease progression in a subset of patients with IPF.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ortega Mateo A, deArtinano AA. Highlights on endothelins: a review. Pharmacol Res 1997; 36: 339–51

    Article  Google Scholar 

  2. Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 2001; 41: 851–76

    Article  PubMed  CAS  Google Scholar 

  3. Teder P, Noble PW. A cytokine reborn? Endothelin-1 in pulmonary inflammation and fibrosis. Am J Respir Cell Mol Biol 2000; 23: 7–10

    PubMed  CAS  Google Scholar 

  4. Baynash A, Hammer R, Richardson J, et al. Severe growth retardation and juvenile lethality in ET-2 knockout mice. Fifth International Conference on Endothelins; 1997 Sep 12–15; Kyoto

  5. Matsumoto H, Suzuki N, Onda H, et al. Abundance of endothelin-3 in rat intestine, pituitary gland and brain. Biochem Biophys Res Commun 1989; 164: 74–80

    Article  PubMed  CAS  Google Scholar 

  6. Battistini B, Dussault P. Biosynthesis, distribution and metabolism of endothelins in the pulmonary system. Pulm Pharmacol Ther 1998; 11: 79–88

    Article  PubMed  CAS  Google Scholar 

  7. Ehrenreich H, Anderson RW, Fox CH, et al. Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med 1990; 172: 1741–8

    Article  PubMed  CAS  Google Scholar 

  8. Giaid A, Michel RP, Stewart DJ, et al. Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet 1993; 341: 1550–4

    Article  PubMed  CAS  Google Scholar 

  9. Sessa WC, Kaw S, Hecker M, et al. The biosynthesis of endothelin-1 by human polymorphonuclear leukocytes. Biochem Biophys Res Commun 1991; 174: 613–8

    Article  PubMed  CAS  Google Scholar 

  10. Harrison VJ, Corder R, Anggard EE, et al. Evidence for vesicles that transport endothelin-1 in bovine aortic endothelial cells. J Cardiovasc Pharmacol 1993; 22 Suppl. 8: S57–60

    Article  Google Scholar 

  11. Wagner OF, Christ G, Wojta J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 1992; 267: 16066–8

    PubMed  CAS  Google Scholar 

  12. Arai H, Hori S, Aramori I, et al. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348: 730–2

    Article  PubMed  CAS  Google Scholar 

  13. Sakurai T, Yanagisawa M, Takuwa Y, et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 1990; 348: 732–5

    Article  PubMed  CAS  Google Scholar 

  14. Katwa LC, Guarda E, Weber KT. Endothelin receptors in cultured adult rat cardiac fibroblasts. Cardiovasc Res 1993; 27: 2125–9

    Article  PubMed  CAS  Google Scholar 

  15. Masaki T, Miwa S, Sawamura T, et al. Subcellular mechanisms of endothelin action in vascular system. Eur J Pharmacol 1999; 375: 133–8

    Article  PubMed  CAS  Google Scholar 

  16. Ergul A, Glassberg MK, Wanner A, et al. Characterization of endothelin receptor subtypes on airway smooth muscle cells. Exp Lung Res 1995; 21: 453–68

    Article  PubMed  CAS  Google Scholar 

  17. Goldie RG, Henry PJ, Knott PG, et al. Endothelin-1 receptor density, distribution, and function in human isolated asthmatic airways. Am J Respir Crit Care Med 1995; 152: 1653–8

    PubMed  CAS  Google Scholar 

  18. Berti F, Rossoni G, Della Bella D, et al. Nitric oxide and prostacyclin influence coronary vasomotor tone in perfused rabbit heart and modulate endothelin-1 activity. J Cardiovasc Pharmacol 1993; 22: 321–6

    Article  PubMed  CAS  Google Scholar 

  19. Filep JG, Bodolay E, Sipka S, et al. Plasma endothelin correlates with antiendothelial antibodies in patients with mixed connective tissue disease. Circulation 1995; 92: 2969–74

    Article  PubMed  CAS  Google Scholar 

  20. Wenzel RR, Fleisch M, Shaw S, et al. Hemodynamic and coronary effects of the endothelin antagonist bosentan in patients with coronary artery disease. Circulation 1998; 98: 2235–40

    Article  PubMed  CAS  Google Scholar 

  21. Dupuis J, Stewart DJ, Cernacek P, et al. Human pulmonary circulation is an important site for both clearance and production of endothelin-1. Circulation 1996; 94: 1578–84

    Article  PubMed  CAS  Google Scholar 

  22. Razzaque MS, Taguchi T. Pulmonary fibrosis: cellular and molecular events. Pathol Int 2003; 53: 133–45

    Article  PubMed  CAS  Google Scholar 

  23. Clark R. Wound repair; overview and general considerations: the molecular and cellular biology of wound repair. London: Plenum Press, 1996: 3–50

    Google Scholar 

  24. Moulin V. Growth factors in skin wound healing. Eur J Cell Biol 1995; 68: 1–7

    Article  PubMed  CAS  Google Scholar 

  25. Greenhalgh DG. The role of growth factors in wound healing. J Trauma 1996; 41: 159–67

    Article  PubMed  CAS  Google Scholar 

  26. Badylak SF. The extracellular matrix as a scaffold for tissue reconstruction. Semin Cell Dev Biol 2002; 13: 377–83

    Article  PubMed  CAS  Google Scholar 

  27. Shi-Wen X, Chen Y, Denton CP, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell 2004; 15: 2707–19

    Article  PubMed  Google Scholar 

  28. Tomasek JJ, Gabbiani G, Hinz B, et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002; 3: 349–63

    Article  PubMed  CAS  Google Scholar 

  29. Desmouliere A. Factors influencing myofibroblast differentiation during wound healing and fibrosis. Cell Biol Int 1995; 19: 471–6

    Article  PubMed  CAS  Google Scholar 

  30. Hafstrom I, Ringertz B, Lundeberg T, et al. The effect of endothelin, neuropeptide Y, calcitonin gene-related peptide and substance P on neutrophil functions. Acta Physiol Scand 1993; 148: 341–6

    Article  PubMed  CAS  Google Scholar 

  31. McMillen MA, Sumpio BE. Endothelins: polyfunctional cytokines. J Am Coll Surg 1995; 180: 621–37

    PubMed  CAS  Google Scholar 

  32. Shahar I, Fireman E, Topilsky M, et al. Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases. Int J Immunopharmacol 1999; 21: 759–75

    Article  PubMed  CAS  Google Scholar 

  33. Peacock AJ, Dawes KE, Shock A, et al. Endothelin-1 and endothelin-3 induce chemotaxis and replication of pulmonary artery fibroblasts. Am J Respir Cell Mol Biol 1992; 7: 492–9

    PubMed  CAS  Google Scholar 

  34. Cambrey AD, Harrison NK, Dawes KE, et al. Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 1994; 11: 439–45

    PubMed  CAS  Google Scholar 

  35. Dawes KE, Cambrey AD, Campa JS, et al. Changes in collagen metabolism in response to endothelin-1: evidence for fibroblast heterogeneity. Int J Biochem Cell Biol 1996; 28: 229–38

    Article  PubMed  CAS  Google Scholar 

  36. Kahaleh MB. Endothelin, an endothelial-dependent vasoconstrictor in scleroderma: enhanced production and profibrotic action. Arthritis Rheum 1991; 34: 978–83

    Article  PubMed  CAS  Google Scholar 

  37. Schmitt-Graff A, Desmouliere A, Gabbiani G. Heterogeneity of myofibroblast phenotypic features: an example of fibroblastic cell plasticity. Virchows Arch 1994; 425: 3–24

    Article  PubMed  CAS  Google Scholar 

  38. Kulasekaren P, Scavone CA, Rogers DS, et al. Endothelin-1 and TGF-β1 independently induce fibroblast resistance to apoptosis via AKT activation. Am J Respir Cell Mol Biol 2009; 41: 484–93

    Article  Google Scholar 

  39. Rodriguez-Pascual F, Redondo-Horcajo M, Lamas S. Functional cooperation between Smad proteins and activator protein-1 regulates transforming growth factor-beta-mediated induction of endothelin-1 expression. Circ Res 2003; 92: 1288–95

    Article  PubMed  CAS  Google Scholar 

  40. Hocher B, Schwarz A, Fagan KA, et al. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol 2000; 23: 19–26

    PubMed  CAS  Google Scholar 

  41. Park SH, Saleh D, Giaid A, et al. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997; 156: 600–8

    PubMed  CAS  Google Scholar 

  42. Mutsaers SE, Marshall RP, Goldsack NR, et al. Effect of endothelin receptor antagonists (BQ-485, Ro 47-0203) on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Pulm Pharmacol Ther 1998; 11: 221–5

    Article  PubMed  CAS  Google Scholar 

  43. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134: 136–51

    PubMed  CAS  Google Scholar 

  44. Selman M, Pardo A. The epithelial/fibroblastic pathway in the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2003; 29: S93–7

    PubMed  CAS  Google Scholar 

  45. Clozel M, Salloukh H. Role of endothelin in fibrosis and anti-fibrotic potential of bosentan. Ann Med 2005; 37: 2–12

    Article  PubMed  CAS  Google Scholar 

  46. Vancheeswaran R, Azam A, Black C, et al. Localization of endothelin-1 and its binding sites in scleroderma skin. J Rheumatol 1994; 21: 1268–76

    PubMed  CAS  Google Scholar 

  47. Abraham DJ, Vancheeswaran R, Dashwood MR, et al. Increased levels of endothelin-1 and differential endothelin type A and B receptor expression in scleroderma-associated fibrotic lung disease. Am J Pathol 1997; 151: 831–41

    PubMed  CAS  Google Scholar 

  48. Carpagnano GE, Kharitonov SA, Wells AU, et al. Increased vitronectin and endothelin-1 in the breath condensate of patients with fibrosing lung disease. Respiration 2003; 70: 154–60

    Article  PubMed  CAS  Google Scholar 

  49. Giaid A, Polak JM, Gaitonde V, et al. Distribution of endothelin-like immunoreactivity and mRNA in the developing and adult human lung. Am J Respir Cell Mol Biol 1991; 4: 50–8

    PubMed  CAS  Google Scholar 

  50. Saleh D, Furukawa K, Tsao MS, et al. Elevated expression of endothelin-1 and endothelin-converting enzyme-1 in idiopathic pulmonary fibrosis: possible involvement of proinflammatory cytokines. Am J Respir Cell Mol Biol 1997; 16: 187–93

    PubMed  CAS  Google Scholar 

  51. Uguccioni M, Pulsatelli L, Grigolo B, et al. Endothelin-1 in idiopathic pulmonary fibrosis. J Clin Pathol 1995; 48: 330–4

    Article  PubMed  CAS  Google Scholar 

  52. Seibold JR, Black CM, Denton CP, et al. Bosentan versus placebo in interstitial lung disease secondary to systemic sclerosis: the BUILD 2 study. Proc Am Thor Soc 2006; 3: A243

    Google Scholar 

  53. King Jr TE, Behr J, Brown KK, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 177: 75–81

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dr Swigris has served as a paid consultant for Actelion Pharmaceuticals, Inc., and is a site Principal Investigator for a trial of bosentan in idiopathic pulmonary fibrosis. Dr Brown has served as a consultant and Protocol Steering Committee member for both Actelion Pharmaceuticals and Gilead Sciences, Inc.

Author information

Authors and Affiliations

  1. Interstitial Lung Disease Program, National Jewish Health, 1400 Jackson Street, Denver, Colorado, 80206, USA

    Jeffrey J. Swigris & Kevin K. Brown

Authors
  1. Jeffrey J. Swigris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin K. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey J. Swigris.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Swigris, J.J., Brown, K.K. The Role of Endothelin-1 in the Pathogenesis of Idiopathic Pulmonary Fibrosis. BioDrugs 24, 49–54 (2010). https://doi.org/10.2165/11319550-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11319550-000000000-00000

Keywords

Search

Navigation