Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Prostaglandin F receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-β

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function1. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed1. Although transforming growth factor-β (TGF-β) functions are crucial in fibrosis2,3, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely4,5,6,7, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A2 (cPLA2) suppresses bleomycin-induced pulmonary fibrosis8, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor9,10,11,12,13,14,15. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-β stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-β signaling additively decrease fibrosis. Furthermore, PGF is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-β. These findings show that PGF-FP signaling facilitates pulmonary fibrosis independently of TGF-β and suggests this signaling pathway as a therapeutic target for IPF.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Bleomycin-induced pulmonary fibrosis in Ptgfr−/− mice.
Figure 2: TGF-β1–independent action of FP signaling in pulmonary fibrosis.
Figure 3: Effects of PGF on proliferation and collagen production of lung fibroblasts.

Similar content being viewed by others

Antoni Torres, Catia Cilloniz, … Tom van der Poll

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Selman, M., King, T.E. & Pardo, A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann. Intern. Med. 134, 136–151 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Border, W.A. & Noble, N.A. Transforming growth factor β in tissue fibrosis. N. Engl. J. Med. 331, 1286–1292 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Munger, J.S. et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Giri, S.N., Hyde, D.M. & Hollinger, M.A. Effect of antibody to transforming growth factor β on bleomycin induced accumulation of lung collagen in mice. Thorax 48, 959–966 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang, Q. et al. Reduction of bleomycin induced lung fibrosis by transforming growth factor β soluble receptor in hamsters. Thorax 54, 805–812 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nakao, A. et al. Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J. Clin. Invest. 104, 5–11 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kapoun, A.M. et al. Transforming growth factor-β receptor type 1 (TGFβRI) kinase activity but not p38 activation is required for TGFβRI-induced myofibroblast differentiation and profibrotic gene expression. Mol. Pharmacol. 70, 518–531 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Nagase, T. et al. A pivotal role of cytosolic phospholipase A2 in bleomycin-induced pulmonary fibrosis. Nat. Med. 8, 480–484 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Hizaki, H. et al. Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP2. Proc. Natl. Acad. Sci. USA 96, 10501–10506 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ushikubi, F. et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 395, 281–284 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Segi, E. et al. Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice. Biochem. Biophys. Res. Commun. 246, 7–12 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Matsuoka, T. et al. Prostaglandin D2 as a mediator of allergic asthma. Science 287, 2013–2017 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Sugimoto, Y. et al. Failure of parturition in mice lacking the prostaglandin F receptor. Science 277, 681–683 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Murata, T. et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388, 678–682 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Kabashima, K. et al. Thromboxane A2 modulates interaction of dendritic cells and T cells and regulates acquired immunity. Nat. Immunol. 4, 694–701 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Narumiya, S. Physiology and pathophysiology of prostanoid receptors. Proc. Jpn. Acad. Ser. B. 83, 296–319 (2007).

    Article  CAS  Google Scholar 

  17. Kabashima, K. et al. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J. Clin. Invest. 109, 883–893 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kita, Y. et al. Pathway-oriented profiling of lipid mediators in macrophages. Biochem. Biophys. Res. Commun. 330, 898–906 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yoshikawa, K., Kita, Y., Kishimoto, K. & Shimizu, T. Profiling of eicosanoid production in the rat hippocampus during kainic acid–induced seizure: dual phase regulation and differential involvement of COX-1 and COX-2. J. Biol. Chem. 281, 14663–14669 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Aono, Y. et al. Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. Am. J. Respir. Crit. Care Med. 171, 1279–1285 (2005).

    Article  PubMed  Google Scholar 

  21. DaCosta Byfield, S., Major, C., Laping, N.J. & Roberts, A.B. SB-505124 is a selective inhibitor of transforming growth factor-β type I receptors ALK4, ALK5 and ALK7. Mol. Pharmacol. 65, 744–752 (2003).

    Article  Google Scholar 

  22. Griffin, B.W., Klimko, P., Crider, J.Y. & Sharif, N.A. AL-8810: a novel prostaglandin F2α analog with selective antagonist effects at the prostaglandin F2α (FP) receptor. J. Pharmacol. Exp. Ther. 290, 1278–1284 (1999).

    CAS  PubMed  Google Scholar 

  23. Jinnin, M. et al. Potential regulatory elements of the constitutive up-regulated α2I collagen gene in scleroderma dermal fibroblasts. Biochem. Biophys. Res. Commun. 343, 904–909 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Ihn, H. et al. Transcriptional regulation of the human α2I collagen gene. Combined action of upstream stimulatory and inhibitory cis-acting elements. J. Biol. Chem. 271, 26717–26723 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Ishizaki, T. et al. Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol. Pharmacol. 57, 976–983 (2000).

    CAS  PubMed  Google Scholar 

  26. Jinnin, M., Ihn, H. & Tamaki, K. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-β1–induced extracellular matrix expression. Mol. Pharmacol. 69, 597–607 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Ley, K. & Zarbock, A. From injury to fibrosis. Nat. Med. 14, 20–21 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Bhatt, N. et al. Promising pharmacologic innovations in treating pulmonary fibrosis. Curr. Opin. Pharmacol. 6, 284–292 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Border, W.A. & Noble, N.A. Targeting TGF-β for treatment of disease. Nat. Med. 1, 1000–1001 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Wyss-Coray, T. et al. TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice. Nat. Med. 7, 612–618 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Moore, B.B. et al. Bleomycin-induced E prostanoid receptor changes alter fibroblast responses to prostaglandin E2 . J. Immunol. 174, 5644–5649 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Lovgren, A.K. et al. COX-2–derived prostacyclin protects against bleomycin-induced pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L144–L156 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Peters-Golden, M. et al. Protection from pulmonary fibrosis in leukotriene-deficient mice. Am. J. Respir. Crit. Care Med. 165, 229–235 (2002).

    Article  PubMed  Google Scholar 

  34. Beller, T.C. et al. Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J. Biol. Chem. 279, 46129–46134 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Tager, A.M. et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat. Med. 14, 45–54 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Handa, T. et al. Polymorphisms of B7 (CD80 and CD86) genes do not affect disease susceptibility to sarcoidosis. Respiration 72, 243–248 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Trojanowska (Medical University of South Carolina) and H. Ihn (Kumamoto University) for the −3500COL1A2/CAT construct, and Ono Pharmaceutical Company for ONO-AE3-208. We also thank Y. Kobashi for BALF analysis, T. Fujiwara for animal care and T. Arai for assistance. This work was supported in part by a Grant-in-Aid for Scientific Research (18002015) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant of the Program for Promotion of Fundamental Studies in Health Science from the National Institute of Biomedical Innovation of Japan and a grant from Ono Research Foundation.

Author information

Authors and Affiliations

Authors

Contributions

Experimental design and discussion: T.O., T.M. and S.N.; performance of experiments and data analysis and interpretation: T.O. (for bleomycin experiments, cell culture and microarray analysis), T.M. (for promoter assays), C.Y. (for RT-PCR), K.N. (for microarray analysis and western blotting), S.K. (for X-gal staining), D.S. (for cell proliferation assays and flow cytometry), Y.K. and T.S. (for liquid chromatography–tandem mass spectrometry analysis), K.T. and Y.T. (for BALF from human subjects), K.C. and M.M. (for analysis of lung function); manuscript preparation: T.O., T.M. and S.N.

Corresponding author

Correspondence to Shuh Narumiya.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Tables 1–4 and Supplementary Figures 1–5 (PDF 3387 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oga, T., Matsuoka, T., Yao, C. et al. Prostaglandin F receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-β. Nat Med 15, 1426–1430 (2009). https://doi.org/10.1038/nm.2066

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2066

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing