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.

Katarzyna Wójcik-Pszczoła,Elżbieta Pękala,Paweł E Ferdek,Agnieszka A Kusiak,Artur Świerczek,Marietta Ślusarczyk,Krzysztof Pociecha,Elżbieta Wyska,Grażyna Chłoń-Rzepa,Reinoud Gosens,Agnieszka Jankowska,Paulina Koczurkiewicz-Adamczyk

doi:10.3390/ijms21114008

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.

Highlights

Cyclic nucleotide phosphodiesterases (PDEs) are cellular enzymes responsible for the hydrolysis of phosphodiester bonds in two second messengers‘—adenosine 3,5 -cyclic monophosphate or guanosine 3,5 -cyclic monophosphate
A substantial body of evidence indicates that elevated cAMP levels promote airway smooth muscle cell (ASMC) relaxation and decrease ASMC/lung fibroblast proliferation, migration, and the ability to synthesize extracellular matrix (ECM) proteins, as well as reduce lung fibroblast to myofibroblast transition (FMT) [2,3,5]
In the lungs or bronchi, remodeling in asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis is often associated with the imbalance in ECM protein turnover, disturbances that occur in the structure and functions of the epithelial layer, smooth muscle cell hyperplasia and hypertrophy, and increased levels of tissue myofibroblasts, predominantly as a result of fibroblast to myofibroblast transition [27,28]

Summary

Introduction

Cyclic nucleotide phosphodiesterases (PDEs) are cellular enzymes responsible for the hydrolysis of phosphodiester bonds in two second messengers‘—adenosine 3 ,5 -cyclic monophosphate (cAMP) or guanosine 3 ,5 -cyclic monophosphate (cGMP). The range of available inhibitors and their therapeutic potential is enormous [1]. The cAMP was reported to be involved in regulating the function of both inflammatory cells as well as lung and bronchi structural cells in respiratory diseases, which inspired a growing interest in the potential therapeutic applications of PDE inhibitors [3,4]. CGMP inhibitors are currently receiving increasingly more interest [1,4,6], owing to the facts that (1) cigarette smoking was associated with a decreased level of guanylyl cyclase [7] and (2) that stimulation of this cGMP-producing enzyme can reduce oxidative stress in chronic obstructive pulmonary disease (COPD) [8]. It is known that smoking can induce PDE3 and PDE4 expression in the lungs [9], which indicates PDEs involvement in COPD but is good further evidence confirming the validity of using PDE inhibitors in the treatment of lung diseases

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