Tags

Type your tag names separated by a space and hit enter

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.
Int J Mol Sci. 2020 Jun 03; 21(11)IJ

Abstract

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-a pan-PDE inhibitor, 869-a TRPA1 modulator, and 145-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 β1 (TGF-β1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-β 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.

Authors+Show Affiliations

Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32503342

Citation

Wójcik-Pszczoła, Katarzyna, et al. "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." International Journal of Molecular Sciences, vol. 21, no. 11, 2020.
Wójcik-Pszczoła K, Chłoń-Rzepa G, Jankowska A, et al. 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. Int J Mol Sci. 2020;21(11).
Wójcik-Pszczoła, K., Chłoń-Rzepa, G., Jankowska, A., Ślusarczyk, M., Ferdek, P. E., Kusiak, A. A., Świerczek, A., Pociecha, K., Koczurkiewicz-Adamczyk, P., Wyska, E., Pękala, E., & Gosens, R. (2020). 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. International Journal of Molecular Sciences, 21(11). https://doi.org/10.3390/ijms21114008
Wójcik-Pszczoła K, et al. 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. Int J Mol Sci. 2020 Jun 3;21(11) PubMed PMID: 32503342.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Wójcik-Pszczoła,Katarzyna, AU - Chłoń-Rzepa,Grażyna, AU - Jankowska,Agnieszka, AU - Ślusarczyk,Marietta, AU - Ferdek,Paweł E, AU - Kusiak,Agnieszka A, AU - Świerczek,Artur, AU - Pociecha,Krzysztof, AU - Koczurkiewicz-Adamczyk,Paulina, AU - Wyska,Elżbieta, AU - Pękala,Elżbieta, AU - Gosens,Reinoud, Y1 - 2020/06/03/ PY - 2020/05/11/received PY - 2020/05/30/revised PY - 2020/05/31/accepted PY - 2020/6/7/entrez PY - 2020/6/7/pubmed PY - 2021/4/1/medline KW - COPD KW - TGF-β KW - TRPA1 channels KW - airway remodeling KW - asthma KW - cAMP KW - calcium influx KW - fibroblast-to-myofibroblast transition KW - myofibroblasts KW - phosphodiesterases JF - International journal of molecular sciences JO - Int J Mol Sci VL - 21 IS - 11 N2 - 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-a pan-PDE inhibitor, 869-a TRPA1 modulator, and 145-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 β1 (TGF-β1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-β 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/32503342/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_ L2 - https://www.mdpi.com/resolver?pii=ijms21114008 DB - PRIME DP - Unbound Medicine ER -