Molecular Medicine

, Volume 21, Issue 1, pp 576–583 | Cite as

Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis

  • Cong Lin
  • Jan von der Thüsen
  • Joost Daalhuisen
  • Marieke ten Brink
  • Bruno Crestani
  • Tom van der Poll
  • Keren Borensztajn
  • C. Arnold Spek
Research Article


Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2 deficiency persistently reduces bleomycin-induced pulmonary fibrosis or merely delays disease progression and whether pharmacological PAR-2 inhibition limits experimental pulmonary fibrosis. Bleomycin was instilled intranasally into wild-type or PAR-2-deficient mice in the presence/absence of a specific PAR-2 antagonist (P2pal-18S). Pulmonary fibrosis was consistently reduced in PAR-2-deficient mice throughout the fibrotic phase, as evident from reduced Ashcroft scores (29%) and hydroxyproline levels (26%) at d 28. Moreover, P2pal-18S inhibited PAR-2-induced profibrotic responses in both murine and primary human pulmonary fibroblasts (p < 0.05). Once daily treatment with P2pal-18S reduced the severity and extent of fibrotic lesions in lungs of bleomycin-treated wild-type mice but did not further reduce fibrosis in PAR-2-deficient mice. Importantly, P2pal-18S treatment starting even 7 d after the onset of fibrosis limits pulmonary fibrosis as effectively as when treatment was started together with bleomycin instillation. Overall, PAR-2 contributes to the progression of pulmonary fibrosis, and targeting PAR-2 may be a promising therapeutic strategy for treating pulmonary fibrosis.



This work was supported by grant from TiPharma (T1-215-1) and the Netherlands Organization for Scientific Research (016.136.167).

Supplementary material

10020_2015_2101576_MOESM1_ESM.pdf (423 kb)
Supplementary material, approximately 422 KB.


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Authors and Affiliations

  • Cong Lin
    • 1
  • Jan von der Thüsen
    • 2
  • Joost Daalhuisen
    • 1
  • Marieke ten Brink
    • 1
  • Bruno Crestani
    • 3
  • Tom van der Poll
    • 1
  • Keren Borensztajn
    • 1
    • 4
    • 5
  • C. Arnold Spek
    • 1
  1. 1.Center for Experimental and Molecular MedicineAcademic Medical CenterAmsterdamThe Netherlands
  2. 2.Department of PathologyErasmus Medical CentreRotterdamThe Netherlands
  3. 3.Assistance Publique-Hôpitaux de Paris, Department of Pulmonology A, Reference Center for Rare Lung DiseasesBichat-Claude Bernard University HospitalParisFrance
  4. 4.Medical School Xavier BichatInserm UMR1152ParisFrance
  5. 5.Département Hospitalo-universtaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx InflamexParisFrance

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