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

Abstract
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.
AuthorsCong Lin, Jan von der Thüsen, Joost Daalhuisen, Marieke ten Brink, Bruno Crestani, Tom van der Poll, Keren Borensztajn, C Arnold Spek
JournalMolecular medicine (Cambridge, Mass.) (Mol Med) Vol. 21 Pg. 576-83 (Jun 29 2015) ISSN: 1528-3658 [Electronic] England
PMID26147947 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Lipopeptides
  • P2pal-18S pepducin
  • Receptor, PAR-2
  • Bleomycin
Topics
  • Animals
  • Bleomycin (toxicity)
  • Fibroblasts (drug effects, metabolism)
  • Humans
  • Idiopathic Pulmonary Fibrosis (chemically induced, drug therapy, genetics)
  • Lipopeptides (administration & dosage)
  • Mice
  • Receptor, PAR-2 (antagonists & inhibitors, genetics)

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