PMID- 30984775
OWN - NLM
STAT- MEDLINE
DCOM- 20190816
LR  - 20200225
IS  - 2314-6141 (Electronic)
IS  - 2314-6133 (Print)
VI  - 2019
DP  - 2019
TI  - Combined Activation of Guanylate Cyclase and Cyclic AMP in Lung Fibroblasts as a 
      Novel Therapeutic Concept for Lung Fibrosis.
PG  - 1345402
LID - 10.1155/2019/1345402 [doi]
LID - 1345402
AB  - 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-beta 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-beta 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-beta 
      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-beta 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-beta induced expression of fibrilar alpha-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-beta induced beta-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.
FAU - Lambers, Christopher
AU  - Lambers C
AUID- ORCID: 0000-0001-5866-5417
AD  - Division of Thoracic Surgery, Department of Surgery, Medical University of 
      Vienna, Austria.
FAU - Boehm, Panja M
AU  - Boehm PM
AD  - Division of Thoracic Surgery, Department of Surgery, Medical University of 
      Vienna, Austria.
FAU - Karabacak, Yasemin
AU  - Karabacak Y
AD  - Center for Molecular Biology, University of Vienna, Austria.
FAU - Samaha, Eslam
AU  - Samaha E
AD  - Division of Respiratory Medicine, Department of Internal Medicine II, Medical 
      University of Vienna, Austria.
FAU - Benazzo, Alberto
AU  - Benazzo A
AD  - Division of Thoracic Surgery, Department of Surgery, Medical University of 
      Vienna, Austria.
FAU - Jaksch, Peter
AU  - Jaksch P
AD  - Division of Thoracic Surgery, Department of Surgery, Medical University of 
      Vienna, Austria.
FAU - Roth, Michael
AU  - Roth M
AUID- ORCID: 0000-0002-8139-2821
AD  - Pulmonary Cell Research, Department of Biomedicine and Pneumology, Department of 
      Internal Medicine, University Hospital and University of Basel, Switzerland.
LA  - eng
PT  - Journal Article
DEP - 20190307
PL  - United States
TA  - Biomed Res Int
JT  - BioMed research international
JID - 101600173
RN  - 0 
      (3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine)
RN  - 0 (Collagen Type I)
RN  - 0 (Collagen Type III)
RN  - 0 (Fibronectins)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridines)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (beta Catenin)
RN  - 1F7A44V6OU (Colforsin)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 4.6.1.2 (Guanylate Cyclase)
MH  - Cell Proliferation/*drug effects/genetics
MH  - Cell Survival/drug effects
MH  - Colforsin/pharmacology
MH  - Collagen Type I/metabolism
MH  - Collagen Type III/metabolism
MH  - Cyclic AMP/genetics
MH  - Fibroblasts/drug effects/metabolism/pathology
MH  - Fibronectins/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Guanylate Cyclase/genetics/metabolism
MH  - Humans
MH  - Idiopathic Pulmonary Fibrosis/*drug therapy/genetics/pathology
MH  - Lung/*drug effects/metabolism/pathology
MH  - Primary Cell Culture
MH  - Pyrazoles/pharmacology
MH  - Pyridines/pharmacology
MH  - Signal Transduction/drug effects
MH  - Transforming Growth Factor beta/*genetics
MH  - beta Catenin/genetics
PMC - PMC6431482
EDAT- 2019/04/16 06:00
MHDA- 2019/08/17 06:00
PMCR- 2019/03/07
CRDT- 2019/04/16 06:00
PHST- 2018/08/15 00:00 [received]
PHST- 2018/12/19 00:00 [revised]
PHST- 2019/01/28 00:00 [accepted]
PHST- 2019/04/16 06:00 [entrez]
PHST- 2019/04/16 06:00 [pubmed]
PHST- 2019/08/17 06:00 [medline]
PHST- 2019/03/07 00:00 [pmc-release]
AID - 10.1155/2019/1345402 [doi]
PST - epublish
SO  - Biomed Res Int. 2019 Mar 7;2019:1345402. doi: 10.1155/2019/1345402. eCollection 
      2019.