title: 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.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cong
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: von der Thüsen
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Daalhuisen
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: ten Brink
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Pulmonology A, Reference Center for Rare Lung Diseases, Bichat-Claude Bernard University Hospital, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.|Inserm UMR1152, Medical School Xavier Bichat, Paris, France.|Département Hospitalo-universtaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France.
authors.forename: Keren
authors.initials: K
authors.lastname: Borensztajn
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: C Arnold
authors.initials: CA
authors.lastname: Spek
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D055666:Lipopeptides / Q000008:administration & dosage*; D051379:Mice; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D055666:Lipopeptides; C580591:P2pal-18S pepducin; D044464:Receptor, PAR-2; D001761:Bleomycin