PDE4 inhibitors roflumilast and rolipram augment PGE(2) inhibition of TGF-beta 1-stimulated fibroblasts

Togo S, Liu X, Wang X, Sugiura H, Kamio K, Kawasaki S, Kobayashi T, Ertl RF, Ahn Y, Holz O, Magnussen H, Fredriksson K, Skold CM, Rennard SI. PDE4 inhibitors roflumilast and rolipram augment PGE(2) inhibition of TGF-beta 1-stimulated fibroblasts. Am J Physiol Lung Cell Mol Physiol 296: L959-L969, 2009. First published March 20, 2009; doi: 10.1152/ajplung.00508.2007.-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)-beta 1, 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-beta 1. 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 similar to 10-fold more potent than rolipram. There was a trend for PDE4 inhibitors to inhibit more in the presence of TGF-beta 1 (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-beta 1-induced PGE(2) production. PDE4 inhibitors together with TGF-beta 1 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-beta 1-induced fibroblast stimulation.