PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts

1 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska; 2 Third Department of Internal Medicine, Wakayama Medical University, Wakayama; 3 Division of Pulmonary Medicine, Department of Internal Medicine, Nippon Medical School, Tokyo; and 4 Third Department of Internal Medicine, Mie University Graduate School of Medicine, Mie, Japan; 5 Center for Pneumology and Thoracic Surgery, Hospital Grosshansdorf, Grosshansdorf, Germany; and 6 Division of Respiratory Medicine, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden Submitted 10 December 2007 ; accepted in final form 2 March 2009 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)-β1, 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-β1. 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 10-fold more potent than rolipram. There was a trend for PDE4 inhibitors to inhibit more in the presence of TGF-β1 (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-β1-induced PGE 2 production. PDE4 inhibitors together with TGF-β1 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-β1-induced fibroblast stimulation. phosphodiesterase 4; chemotaxis; collagen gel contraction; transforming growth factor-β1; prostaglandin E 2 Address for reprint requests and other correspondence: S. I. Rennard,