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

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.

Phosphodiesterase Inhibitors: Could They Be Beneficial for the Treatment of COVID-19?

“…Wójcik-Pszczoła and coauthors [ 33 ] used three different 7,8-disubstituted purine-2,6-dione derivatives (compound “832”—a pan-selective PDE inhibitor, compound “869”—a TRPA1 modulator and compound “145”—a pan-selective PDE inhibitor and a TRPA1 modulator) and evaluated their ability to inhibit the pro-fibrotic responses of lung fibroblast cell lines and MRC-5 104 cells once activated by TGF-β1 or FBS. In parallel, they studied their proliferation, migration, contraction, expression of profibrotic genes and phenotypic transition into myofibroblasts.…”

“…These data suggest that the TGF-β pathway is an important target for PDE inhibitors, which leads to inhibitory effects on cellular responses involved in airway remodeling. These potent pan-selective PDE inhibitors represent promising anti-remodeling drug candidates for further research, including research on anti-COVID-19 drugs [ 33 ]. Among these pan-selective compounds, sulindac, originally used as anti-inflammatory drug, was shown to be a PDE5 and PDE10 inhibitor [ 46 ].…”

“…Elevated cAMP levels also promote relaxation of lung smooth muscle cells (ASMC) [32] and reduce the proliferation and migration of ASMC cells and/or lung fibroblasts, as well as their ability to synthesize extracellular matrix proteins. In addition, high levels of cAMP strongly reduce the transition of fibroblasts to myofibroblasts [33]. All these observations lead the way to increased interest in PDE inhibitors for the control of respiratory diseases [34,35], However, the most effective inhibitors could be those with broad range that do not inhibit specific isoforms, but are inhibitors of various PDEs, i.e., pan inhibitors.…”

New Avenues for Phosphodiesterase Inhibitors in Asthma

“… 18 A group of potent, pan-PDE inhibitors from the group of 7.8-disubstituted purine-2,6-dione derivatives represent promising anti-remodelling drug candidates for further research. 96 …”

Fibroblast Mechanotransduction Network Predicts Targets for Mechano-Adaptive Infarct Therapies

“…We found that NE acted to antagonize latent TGFβ1 expression via a cAMP-PKA-CREB signaling axis. Activation of CREB through the use of phosphodiesterase inhibitors has previously been shown to antagonize fibrotic expression of lung and cardiac fibroblasts (Miller et al, 2011;Wójcik-Pszczoła et al, 2020) as well as cardiac fibrosis in a pressure overload mouse model (Gong et al, 2014) , suggesting a potential mechano-responsiveness of this mechanism. Simulated fibroblast responses to TGFβ1 indicated a synergistic response under tension with latent TGFβ1 activation and output expression occurring for lower input doses.…”