A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling

Autor: Paulina Koczurkiewicz-Adamczyk, Pawel E. Ferdek, Elżbieta Pękala, Reinoud Gosens, Agnieszka Jankowska, Grażyna Chłoń-Rzepa, Artur Świerczek, Elżbieta Wyska, Krzysztof Pociecha, Marietta Ślusarczyk, Katarzyna Wójcik-Pszczoła, Agnieszka A. Kusiak
Přispěvatelé: Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Phosphodiesterase Inhibitors
Cell
Drug Evaluation
Preclinical
Pharmacology
lcsh:Chemistry
airway remodeling
Transient receptor potential channel
0302 clinical medicine
Cell Movement
Cyclic AMP
Cyclic AMP Response Element-Binding Protein
lcsh:QH301-705.5
Lung
TRPA1 Cation Channel
Spectroscopy
biology
TGF-$\beta$
Chemistry
Phosphodiesterase
General Medicine
Computer Science Applications
medicine.anatomical_structure
030220 oncology & carcinogenesis
medicine.symptom
calcium influx
Signal Transduction
medicine.drug
TGF-β
Cell Survival
myofibroblasts
Inflammation
CREB
Article
Catalysis
Transforming Growth Factor beta1
Inorganic Chemistry
03 medical and health sciences
fibroblast-to-myofibroblast transition
cAMP
medicine
Humans
COPD
phosphodiesterases
Physical and Theoretical Chemistry
Protein kinase A
Molecular Biology
Roflumilast
Cell Proliferation
Cyclic Nucleotide Phosphodiesterases
Type 7
Organic Chemistry
Fibroblasts
asthma
Cyclic AMP-Dependent Protein Kinases
Fibrosis
Cyclic Nucleotide Phosphodiesterases
Type 4
TRPA1 channels
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
3'
5'-Cyclic-AMP Phosphodiesterases
Drug Design
biology.protein
Calcium
Transforming growth factor
Zdroj: International Journal of Molecular Sciences
Volume 21
Issue 11
International Journal of Molecular Sciences, 21(11):4008. MDPI AG
International Journal of Molecular Sciences, Vol 21, Iss 4008, p 4008 (2020)
ISSN: 1422-0067
Popis: Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832&mdash
a pan-PDE inhibitor, 869&mdash
a TRPA1 modulator, and 145&mdash
a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type &beta
1 (TGF-&beta
1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-&beta
pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research.
Databáze: OpenAIRE
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