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Original research
Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension
  1. Wen-Hui Wu1,
  2. Sébastien Bonnet2,
  3. Tsukasa Shimauchi2,
  4. Victoria Toro2,
  5. Yann Grobs2,
  6. Charlotte Romanet2,
  7. Alice Bourgeois2,
  8. Geraldine Vitry2,
  9. Junichi Omura2,
  10. Eve Tremblay2,
  11. Valerie Nadeau2,
  12. Mark Orcholski2,
  13. Sandra Breuils-Bonnet2,
  14. Sandra Martineau2,
  15. Pasquale Ferraro3,
  16. Francois Potus2,
  17. Roxane Paulin2,
  18. Steeve Provencher2,
  19. Olivier Boucherat2
  1. 1Department of Cardio-Pulmonary Circulation, Tongji University School of Medicine, Shanghai, Shanghai, China
  2. 2Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Centre (IUCPQ), Quebec, Quebec, Canada
  3. 3Department of Surgery, University of Montreal, Montreal, Quebec, Canada
  1. Correspondence to Dr Olivier Boucherat, Quebec Heart and Lung Institute Research Centre (IUCPQ), Quebec, QC G1V 4G5, Canada; olivier.boucherat{at}criucpq.ulaval.ca

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH.

Methods and results Increased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH.

Conclusion This study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH.

  • idiopathic pulmonary fibrosis
  • primary pulmonary hypertension

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • SP and OB are joint senior authors.

  • SP and OB contributed equally.

  • Contributors W-HW, SB, SP and OB conceived and designed the research study. W-HW, TS, VT, YG, CR, AB, GV, JO, ET, VN, MO, SB-B and SM were responsible for acquiring, analysing and interpreting the data. PF provided human lung tissues. FP and RP revised the manuscript for important intellectual content. W-HW, SP, SB and OB drafted the manuscript. OB, SP and SB revised the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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