title: The D prostanoid receptor agonist BW245C [(4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid] inhibits fibroblast proliferation and bleomycin-induced lung fibrosis in mice.
abstract: Prostaglandin (PG) D(2) exerts contrasting activities in the inflamed lung via two receptors, the D prostanoid receptor (DP) and the chemoattractant receptor-homologous molecule expressed on T helper 2 lymphocytes. DP activation is known mainly to inhibit proinflammatory cell functions. We tested the effect of a DP-specific agonist, (4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid (BW245C), on pulmonary fibroblast functions in vitro and in a mouse model of lung fibrosis induced by bleomycin. DP mRNA expression was detected in cultured mouse lung primary fibroblasts and human fetal lung fibroblasts and found to be up- and down-regulated by interleukin-13 and transforming growth factor (TGF)-β, respectively. Although micromolar concentrations of BW245C and PGD(2) did not affect mouse fibroblast collagen synthesis or differentiation in myofibroblasts, they both inhibited fibroblast basal and TGF-β-induced proliferation in vitro. The repeated administration of BW245C (500 nmol/kg body weight instilled transorally in the lungs 2 days before and three times per week for 3 weeks) in bleomycin-treated mice significantly decreased both inflammatory cell recruitment and collagen accumulation in the lung (21 days). Our results indicate that BW245C can reduce lung fibrosis in part via its activity on fibroblast proliferation and suggest that DP activation should be considered as a new therapeutic target in fibroproliferative lung diseases.
authors: Louvain Centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, 53.02 Avenue Emmanuel Mounier, B-1200, Brussels, Belgium. sybille.vandenbrule@uclouvain.be
authors: Sybille
authors: S
authors: van den Brule
authors: Laurent
authors: L
authors: Wallemme
authors: Francine
authors: F
authors: Uwambayinema
authors: François
authors: F
authors: Huaux
authors: Dominique
authors: D
authors: Lison
mesh_terms: D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology / Q000627:therapeutic use*; D018793:Interleukin-13 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D006827:Hydantoins; D018793:Interleukin-13; D011982:Receptors, Prostaglandin; D016212:Transforming Growth Factor beta; C527097:prostanoid D receptor 1, mouse; D001761:Bleomycin; C030669:BW 245C; D003094:Collagen