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PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts.
Am J Physiol Lung Cell Mol Physiol 2009; 296(6):L959-69AJ

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+Show Affiliations

Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5885, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19304913

Citation

Togo, Shinsaku, et al. "PDE4 Inhibitors Roflumilast and Rolipram Augment PGE2 Inhibition of TGF-{beta}1-stimulated Fibroblasts." American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 296, no. 6, 2009, pp. L959-69.
Togo S, Liu X, Wang X, et al. PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2009;296(6):L959-69.
Togo, S., Liu, X., Wang, X., Sugiura, H., Kamio, K., Kawasaki, S., ... Rennard, S. I. (2009). PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts. American Journal of Physiology. Lung Cellular and Molecular Physiology, 296(6), pp. L959-69. doi:10.1152/ajplung.00508.2007.
Togo S, et al. PDE4 Inhibitors Roflumilast and Rolipram Augment PGE2 Inhibition of TGF-{beta}1-stimulated Fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2009;296(6):L959-69. PubMed PMID: 19304913.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts. AU - Togo,Shinsaku, AU - Liu,Xiangde, AU - Wang,Xingqi, AU - Sugiura,Hisatoshi, AU - Kamio,Koichiro, AU - Kawasaki,Shin, AU - Kobayashi,Tetsu, AU - Ertl,Ronald F, AU - Ahn,Youngsoo, AU - Holz,Olaf, AU - Magnussen,Helgo, AU - Fredriksson,Karin, AU - Skold,C Magnus, AU - Rennard,Stephen I, Y1 - 2009/03/20/ PY - 2009/3/24/entrez PY - 2009/3/24/pubmed PY - 2009/7/17/medline SP - L959 EP - 69 JF - American journal of physiology. Lung cellular and molecular physiology JO - Am. J. Physiol. Lung Cell Mol. Physiol. VL - 296 IS - 6 N2 - 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. SN - 1040-0605 UR - https://www.unboundmedicine.com/medline/citation/19304913/PDE4_inhibitors_roflumilast_and_rolipram_augment_PGE2_inhibition_of_TGF_{beta}1_stimulated_fibroblasts_ L2 - http://www.physiology.org/doi/full/10.1152/ajplung.00508.2007?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -