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BioMed Research International
Volume 2019, Article ID 1345402, 10 pages
https://doi.org/10.1155/2019/1345402
Research Article

Combined Activation of Guanylate Cyclase and Cyclic AMP in Lung Fibroblasts as a Novel Therapeutic Concept for Lung Fibrosis

1Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Austria
2Center for Molecular Biology, University of Vienna, Austria
3Division of Respiratory Medicine, Department of Internal Medicine II, Medical University of Vienna, Austria
4Pulmonary Cell Research, Department of Biomedicine and Pneumology, Department of Internal Medicine, University Hospital and University of Basel, Switzerland

Correspondence should be addressed to Christopher Lambers; ta.ca.neiwinudem@srebmal.rehpotsirhc

Received 15 August 2018; Revised 19 December 2018; Accepted 28 January 2019; Published 7 March 2019

Academic Editor: Coline van Moorsel

Copyright © 2019 Christopher Lambers et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Remodelling of the peripheral lung tissue and fibrotic foci are the main pathologies of idiopathic pulmonary fibrosis (IPF), a disease that is difficult to treat. TGF-β activation of peripheral lung fibroblasts is indicated as the major cause of tissue remodelling in IPF and is resulting in fibroblast hyperplasia and deposition of extracellular matrix. Soluble guanylate cyclase (sGC) stimulators combined with cyclic AMP (cAMP) activators have been reported to reduce proliferation and matrix deposition in other conditions than IPF. Therefore, this drug combination may present a novel therapeutic concept for IPF. This study investigated the effect of BAY 41-2272 and forskolin on remodelling parameters in primary human lung fibroblasts. The study determined TGF-β induced proliferation by direct cell counts after 3 days; and deposition of collagen type-I, type III, and fibronectin. BAY 41-2272 significantly reduced TGF-β induced fibroblast proliferation, but did not reduce viability. This inhibitory effect was further supported by forskolin. Both BAY 41-2272 and forskolin alone reduced TGF-β induced collagen and fibronectin de novo synthesis as well as deposition. This effect was significantly stronger when the two compounds were combined. Furthermore, the TGF-β induced expression of fibrilar α-smooth muscle actin was reduced by BAY 41-2272 and this effect was strengthened by forskolin. In addition, BAY 41-2272 and forskolin reduced TGF-β induced β-catenin. All effects of BAY 41-2272 were concentration dependent. The findings suggest that BAY 41-2272 in combination with cAMP stimulation may present a novel therapeutic strategy to reduce tissue remodelling in IPF.