The D prostanoid (DP) 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.

Van Den Brûle, Sybille [UCL] Wallemme, Laurent [UCL] Uwambayinema, Francine [UCL] Huaux, François [UCL] Lison, Dominique [UCL]

Prostaglandin (PG) D2 exerts contrasting activities in the inflamed lung via two receptors, the D prostanoid receptor (DP) and the Chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes (CRTH2). DP activation is mainly known to inhibit pro-inflammatory cell functions. We tested here the effect of a DP specific agonist, BW245C ((4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), 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 (HFL-1) and found up- and down-regulated by interleukin-13 and transforming growth factor (TGF)-beta, respectively. While micromolar concentrations of BW245C and PGD2 did not affect mouse fibroblast collagen synthesis or differentiation in myofibroblasts, they both inhibited fibroblast basal and TGF-beta-induced proliferation in vitro. The repeated administration of BW245C (500 nmol/kg bw instilled trans-orally in the lungs 2 days before and 3 times per week during 3 weeks) in bleomycin-treated mice significantly decreased both inflammatory cell recruitment and collagen accumulation in the lung (21 d). 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 fibro-proliferative lung diseases.