Phosphodiesterases as therapeutic targets for respiratory diseases

Zuo, Haoxiao; Cattani‐Cavalieri, Isabella; Musheshe, Nshunge; Nikolaev, Viacheslav O.; Schmidt, Martina

doi:10.1016/j.pharmthera.2019.02.002

Cited by 90 publications

(126 citation statements)

References 261 publications

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“…Anti-inflammatory and anti-fibrotic properties of cAMP were demonstrated in different cellular models [2]. 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]. 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].…”

Section: Introductionmentioning

confidence: 99%

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

Wójcik-Pszczoła

Chłoń-Rzepa

Jankowska

et al. 2020

IJMS

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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.

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Section: Introductionmentioning

confidence: 99%

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

Wójcik-Pszczoła

Chłoń-Rzepa

Jankowska

et al. 2020

IJMS

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“…However, EP 2 -specific agonists should likely be combined with PDE4-specific inhibitors so that cAMP elevation is promoted while simultaneously inhibiting EP 2 -mediated desensitization, thus achieving sustained high levels of cAMP that may be sufficient for reducing fibrotic activity. Selective and combinatorial inhibition of PDE isoforms is gaining traction in a wide array of pulmonary diseases (Zuo et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Agonist-specific desensitization of PGE2-stimulated cAMP signaling due to upregulated phosphodiesterase expression in human lung fibroblasts

Núñez

Schulte

Michalski

et al. 2019

Naunyn-Schmiedeberg's Arch Pharmacol

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Pulmonary fibroblasts play an essential role in maintaining the structure and function of the lung. In idiopathic pulmonary fibrosis, fibroblast cells persist in an activated form and produce excessive fibrous material, leading to loss of alveolar structure. PGE2, which specifically activates EP2 and EP4 receptor subtypes, is a cAMP elevating agent and thus has anti‐fibrotic potential, since cAMP has been shown to have anti‐fibrotic properties. Although PGE2 levels are increased in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis (and in animal models of pulmonary fibrosis), it does not prevent pulmonary fibrosis. One hypothesis is that PGE2 effects are self‐limiting because of desensitization caused by prolonged exposure. To test this hypothesis, we pretreated HFL‐1 fibroblasts with PGE2 and other cAMP‐elevating agents then measured PGE2‐stimulated cAMP levels using the downward cAMP difference detector in situ (cADDis) cAMP sensor (Montana Molecular, Bozeman MT). After 24‐hour pretreatment with 100 nM PGE2, we changed the media and measured cAMP kinetics in response to various concentrations of PGE2. Pretreatment with PGE2 shifted the concentration‐response curve of PGE2 rightward approximately 50‐fold. Neither 100 nM isoproterenol or 1μM forskolin pretreatment for 24 hours altered PGE2 response, implying that other cAMP elevating agents do not induce desensitization. We sought to uncover the underlying mechanism responsible for PGE2 desensitization. Desensitization could result from either receptor internalization through the GRK/β‐arrestin mediated pathway or via increase PDE activity. To determine if PGE2 pretreatment increases PDE activity, we used the PDE3 inhibitor, cilostazol, and the PDE4 inhibitor, rolipram after PGE2 pretreatment. Rolipram, increased both the EC50 and Emax of PGE2 in vehicle pretreated HFL‐1 fibroblasts. In cells pretreated with PGE2, rolipram partially reversed the desensitization, indicating that PDE4 may be induced by long term PGE2 exposure. Cilostazol had minimal effects on either control or desensitized PGE2 responses, implying that PDE3 is not involved. Examination of PDE isoform mRNA levels via quantitative RT‐PCR, show that PGE2 treatment upregulates PDE3A, PDE4C and PDE4D, while pretreatment with isoproterenol or forskolin only upregulated PDE4D. Taken together, these results show that long‐term exposure to PGE2 causes desensitization of EP receptor‐stimulated cAMP signaling, partly through the increased expression of a PDE4 isoform. Defining the precise PDE isoform involved in the desensitization of PGE2 responses may lead to new therapeutic strategies for treating pulmonary fibrosis. Support or Funding Information This work was supported by NIH grant GM107094 (RO) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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“…In fact, roflumilast, which is a PDE4 inhibitor, has been available on the market for a long time for the treatment of COPD. However, we understand that different PDE isozymes selectively regulate cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) signalling in different subcellular microdomains, and individual PDEs are likely involved in specific locations at certain time-points based on different stimulations/activations (figure 2) [8,9]. Furthermore, rather than involving a single PDE, we must consider the participation of multiple PDE variants in a complex signalling network involving central regulatory mechanisms [10,11].…”

Section: Selective Pde Inhibitorsmentioning

confidence: 99%

“…Several compounds that selectively inhibit PDE3 and PDE4, such as zardaverine, benzafentrine, tolafentrine and pumafentrine have been tested in human volunteers but none have progressed to the clinic presumably because of lack of efficacy or concerns about safety [9]. Ensifentrine (RPL554) is the only dual PDE3/PDE4 inhibitor under clinical development for the treatment of COPD, asthma and likely, cystic fibrosis [16].…”

Section: Selective Pde Inhibitorsmentioning

confidence: 99%

“…Ensifentrine (RPL554) is the only dual PDE3/PDE4 inhibitor under clinical development for the treatment of COPD, asthma and likely, cystic fibrosis [16]. However, it has been highlighted that its affinity for PDE3 is 3440-times higher than that for PDE4 (half maximal inhibitory concentration [IC 50 ] for PDE3 0.43 nM and PDE4 1479 nM) [17], which suggests that it acts predominantly as a PDE3 inhibitor and therefore as a bronchodilator [9]. It is worth mentioning that there is preclinical and clinical documentation of a synergistic interaction between ensifentrine and β 2 -adrenoceptor agonists or mAChR antagonists [18][19][20], which suggests it could be used as an add-on agent.…”

Section: Selective Pde Inhibitorsmentioning

confidence: 99%

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The future of bronchodilation: looking for new classes of bronchodilators

2019

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@ERSpublicationsThere is a real interest among researchers and the pharmaceutical industry in developing novel bronchodilators. There are several new opportunities; however, they are mostly in a preclinical phase. They could better optimise bronchodilation. http://bit.ly/2lW1q39Cite this article as: Cazzola M, Rogliani P, Matera MG. The future of bronchodilation: looking for new classes of bronchodilators.ABSTRACT Available bronchodilators can satisfy many of the needs of patients suffering from airway disorders, but they often do not relieve symptoms and their long-term use raises safety concerns. Therefore, there is interest in developing new classes that could help to overcome the limits that characterise the existing classes. At least nine potential new classes of bronchodilators have been identified: 1) selective phosphodiesterase inhibitors; 2) bitter-taste receptor agonists; 3) E-prostanoid receptor 4 agonists; 4) Rho kinase inhibitors; 5) calcilytics; 6) agonists of peroxisome proliferator-activated receptor-γ; 7) agonists of relaxin receptor 1; 8) soluble guanylyl cyclase activators; and 9) pepducins. They are under consideration, but they are mostly in a preclinical phase and, consequently, we still do not know which classes will actually be developed for clinical use and whether it will be proven that a possible clinical benefit outweighs the impact of any adverse effect.It is likely that if developed, these new classes may be a useful addition to, rather than a substitution of, the bronchodilator therapy currently used, in order to achieve further optimisation of bronchodilation.

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Phosphodiesterases as therapeutic targets for respiratory diseases

Cited by 90 publications

References 261 publications

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

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

Agonist-specific desensitization of PGE2-stimulated cAMP signaling due to upregulated phosphodiesterase expression in human lung fibroblasts

The future of bronchodilation: looking for new classes of bronchodilators

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