title: PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts.
abstract: Fibrotic diseases are characterized by the accumulation of extracellular matrix together with distortion and disruption of tissue architecture. Phosphodiesterase (PDE)4 inhibitors, by preventing the breakdown of cAMP, can inhibit fibroblast functions and may be able to mitigate tissue remodeling. Transforming growth factor (TGF)-beta1, a mediator of fibrosis, can potentially modulate cAMP by altering PGE(2) metabolism. The present study assessed whether PDE4 inhibitors functionally antagonize the profibrotic activity of fibroblasts stimulated by TGF-beta1. The PDE4 inhibitors roflumilast and rolipram both inhibited fibroblast-mediated contraction of three-dimensional collagen gels and fibroblast chemotaxis toward fibronectin in the widely studied human fetal lung fibroblast strain HFL-1 and several strains of fibroblasts from adult human lung. Roflumilast was approximately 10-fold more potent than rolipram. There was a trend for PDE4 inhibitors to inhibit more in the presence of TGF-beta1 (0.05 < P < 0.08). The effect of the PDE4 inhibitors was mediated through cAMP-stimulated protein kinase A (PKA), although a PKA-independent effect on gel contraction was also observed. The effect of PDE4 inhibitors depended on fibroblast production of PGE(2) and TGF-beta1-induced PGE(2) production. PDE4 inhibitors together with TGF-beta1 resulted in augmented PGE(2) production together with increased expression of COX mRNA and protein. The present study supports the concept that PDE4 inhibitors may attenuate fibroblast activities that can lead to fibrosis and that PDE4 inhibitors may be particularly effective in the presence of TGF-beta1-induced fibroblast stimulation.
authors.affiliation: Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5885, USA.
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Togo
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.forename: Xingqi
authors.initials: X
authors.lastname: Wang
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Sugiura
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kamio
authors.forename: Shin
authors.initials: S
authors.lastname: Kawasaki
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Ertl
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Ahn
authors.forename: Olaf
authors.initials: O
authors.lastname: Holz
authors.forename: Helgo
authors.initials: H
authors.lastname: Magnussen
authors.forename: Karin
authors.initials: K
authors.lastname: Fredriksson
authors.forename: C Magnus
authors.initials: CM
authors.lastname: Skold
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
mesh_terms: D000328:Adult; D000631:Aminopyridines / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D003521:Cyclopropanes / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004357:Drug Synergism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D005353:Fibronectins; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D053773:Transforming Growth Factor beta1; C424423:Roflumilast; D003094:Collagen; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D015232:Dinoprostone