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.
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Authors | Cong Lin, Jan von der Thüsen, Joost Daalhuisen, Marieke ten Brink, Bruno Crestani, Tom van der Poll, Keren Borensztajn, C Arnold Spek |
Journal | Molecular medicine (Cambridge, Mass.)
(Mol Med)
Vol. 21
Pg. 576-83
(Jun 29 2015)
ISSN: 1528-3658 [Electronic] England |
PMID | 26147947
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Lipopeptides
- P2pal-18S pepducin
- Receptor, PAR-2
- Bleomycin
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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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