Inhibition of TGF-β induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase

Torsten R. Dunkern, Daniel Feurstein, Giovanni A. Rossi, Federica Sabatini, Armin Hatzelmann

Research output: Contribution to journalArticlepeer-review

Abstract

Pulmonary fibroblast to myofibroblast conversion is a pathophysiological feature of idiopathic pulmonary fibrosis and COPD. This conversion is induced by transforming growth factor (TGF)-β derived from epithelial cells as well as activated macrophages that have infiltrated the lung. Preventing this conversion might be a favourable therapeutic approach. Within this study we examined the activity of different members of the phosphodiesterase (PDE) family in primary human lung fibroblasts and various lung fibroblast cell lines both before and after TGF-β induced differentiation to myofibroblasts as reflected by the expression of alpha-smooth muscle actin. We showed that the predominant PDE activities in lung fibroblasts are attributed to PDE5, PDE1 and to a smaller extent to PDE4. cyclic GMP (cGMP)-hydrolyzing activity declines by about half after differentiation to myofibroblasts in all pulmonary fibroblasts investigated, which is accompanied by a down-regulation of PDE5 protein. Lung fibroblast to myofibroblast differentiation is blocked by treatment with the PDE4 inhibitor piclamilast alone, depending on the TGF-β concentration applied, and in combination with prostaglandin E2 (PGE2) in a synergistic manner. Despite the high PDE5 activity the PDE5 inhibitor sildenafil by itself as well as in combination with brain natriuretic peptide or the nitric oxide-donor DETA-NONOate shows no inhibiting effects. However, combining sildenafil with the guanylyl cyclase (GC) activator BAY58-2667 and ODQ (which sensitizes GC for activation by BAY58-2667) suppressed TGF-β induced differentiation. In summary, our data indicate that drugs interfering with the cyclic AMP (cAMP)-as well as with the NO-cGMP-pathway offer the therapeutic opportunity to prevent the differentiation of pulmonary fibroblasts to myofibroblasts in lung fibrosis.

Original languageEnglish
Pages (from-to)12-22
Number of pages11
JournalEuropean Journal of Pharmacology
Volume572
Issue number1
DOIs
Publication statusPublished - Oct 15 2007

Keywords

  • Fibrosis
  • Lung fibroblast
  • Phosphodiesterase
  • Sildenafil
  • TGF-β

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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