Abstract
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 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 PGD2 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.
Footnotes
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This work was supported by Action de Recherche Concertée, Communauté Française de Belgique, and the European Commission under FP7-HEALTH-F4–2008 Resolve [Contract 202047]. F.H. is a Research Associate with the Fonds National de la Recherche Scientifique of Belgium.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.169250
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ABBREVIATIONS:
- PG
- prostaglandin
- DP
- D prostanoid receptor
- BW245C
- (4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid
- CRTH2
- chemoattractant receptor-homologous molecule expressed on T helper 2 lymphocytes
- Th2
- T helper 2
- bleo
- bleomycin
- TGF
- transforming growth factor
- IL
- interleukin
- DC
- dendritic cell
- b.wt.
- body weight
- HFL
- human fetal lung
- 15d-PGJ2
- 15-deoxy-δ-12,14-prostaglandin J2
- PBS
- phosphate-buffered saline
- FBS
- fetal bovine serum
- DMEM
- Dulbecco's modified Eagle's medium
- AA
- antibiotic-antimycotic
- PCR
- polymerase chain reaction
- SMA
- smooth muscle actin
- BAL
- bronchoalveolar lavage
- BALF
- BAL fluid
- LDH
- lactate dehydrogenase
- ELISA
- enzyme-linked immunosorbent assay
- Received April 23, 2010.
- Accepted August 17, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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