title: PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels.
abstract: Therapies that mitigate the fibrotic process may be able to slow progressive loss of function in many lung diseases. Because cyclic adenosine monophosphate is known to regulate fibroblasts, the current study was designed to evaluate the activity of selective phosphodiesterase (PDE) inhibitors on two in vitro fibroblast responses: chemotaxis and contraction of three-dimensional collagen gels. Selective PDE4 inhibitors, rolipram and cilomilast, each inhibited the chemotaxis of human fetal lung fibroblasts (HFL-1) toward fibronectin in the blindwell assay system (control: 100% versus cilomilast [10 microM]: 40.5 +/- 7.3% versus rolipram: [10 microM] 32.1 +/- 2.7% cells/5 high-power fields; P < 0.05, both comparisons). These PDE4 inhibitors also inhibited contraction of three-dimensional collagen gels (control: 100% versus cilomilast: 167.7 +/- 6.9% versus rolipram: 129.9 +/- 1.9% of initial size; P < 0.05, both comparisons). Amrinone, a PDE3 inhibitor, and zaprinast, a PDE5 inhibitor, had no effect in either system. Prostaglandin E(2) (PGE(2)) inhibited both chemotaxis and gel contraction, and the PDE4 inhibitors shifted the PGE(2) concentration-dependence curve to the left in both systems. The inhibition of endogenous PGE(2) production by indomethacin diminished the effects of the PDE4 inhibitors in both chemotaxis and gel contraction, consistent with the concept that the PDE4 inhibitory effects on fibroblasts are related to the presence of cyclic adenosine monophosphate in the cells. In summary, these in vitro results suggest that PDE4 inhibitors may be able to suppress fibroblast activity and, thus, have the potential to block the development of progressive fibrosis.
authors.affiliation: University of Nebraska Medical Center, Omaha 68198-5125, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kohyama
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.forename: Fu-Qiang
authors.initials: FQ
authors.lastname: Wen
authors.forename: Yun Kui
authors.initials: YK
authors.lastname: Zhu
authors.forename: Hangjun
authors.initials: H
authors.lastname: Wang
authors.forename: Hui Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hajime
authors.initials: H
authors.lastname: Takizawa
authors.forename: Lenora B
authors.initials: LB
authors.lastname: Cieslinski
authors.forename: Mary S
authors.initials: MS
authors.lastname: Barnette
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000187:drug effects*; D001483:Base Sequence; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D017931:DNA Primers; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D010726:Phosphodiesterase Inhibitors; D003094:Collagen; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007545:Isoproterenol; D007213:Indomethacin