A pathophysiological role of PDE3 in allergic airway inflammation

Beute, Jan; Lukkes, Melanie; Koekoek, Ewout P.; Nastiti, Hedwika; Ganesh, Keerthana; Bruijn, Marjolein J. W. de; Hockman, Steven; Nimwegen, Menno van; Braunstahl, Gert‐Jan; Boon, Louis; Lambrecht, Bart N.; Manganiello, Vince; KleinJan, Alex

doi:10.1172/jci.insight.94888

Cited by 33 publications

(40 citation statements)

References 85 publications

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“…As mentioned above, the airway smooth muscle (ASM) human cells as well as epithelial cells express PDE4 enzymes (Beute et al, 2018;Mokry et al, 2018). This is consistent with the findings of in vitro experiments showing that ASM human cells are primarily sensitive to cilostamid (PDE3 inhibitor), while both ASM cells and human non-polarized bronchial epithelial (16HBE 14o) cells are responding to PDE4 inhibition by roflumilast.…”

Section: Selective Pde4 Inhibitorssupporting

confidence: 86%

“…In the human airway epithelial cells PDE4 activity is predominantly expressed in addition to lesser PDE1, PDE3, and PDE5 activity ( Table 1) (Wright et al, 1998). The airway smooth muscle (ASM) human cells express both PDE3 and PDE4 enzymes (Beute et al, 2018). As described above, activity of PDE leads to relatively flexible changes in intracellular cAMP concentrations, which are involved in direct modulation of calcium mediated contractions of microtubular apparatus.…”

Section: Pde and Ciliary Motilitymentioning

confidence: 99%

“…Similar results were observed by Schmid et al (2006), who described dose-dependent, albeit similar and simultaneous increases in cAMP and ciliary beat frequency caused by forskolin administration on human airway epithelial cells. Therefore, an inhibition of PDEs, either nonselective or selective to mostly expressed isoforms in the airways, might be potentially useful in the modulation of CBF, either directly by changing the cAMP levels in cilia, or indirectly by influencing the allergic or other inflammation (Beute et al, 2018). Chronic treatment with PDE inhibitors seems to have stronger effect on the ciliary beating since they do not directly increase the generation of cAMP, but decrease its breakdown.…”

Section: Pde and Ciliary Motilitymentioning

confidence: 99%

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Respiratory Cilia as a Therapeutic Target of Phosphodiesterase Inhibitors

2020

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Mucociliary clearance is an essential airway defense mechanism dependent predominantly on the proper ciliary function and mucus rheology. The crucial role of cilia is evident in`a variety of respiratory diseases, as the ciliary dysfunction is associated with a progressive decline in lung function over time. The activity of cilia is under supervision of multiple physiological regulators, including second messengers. Their role is to enable a movement in coordinated metachronal waves at certain beat frequency. Ciliary function can be modulated by various stimuli, including agents from the group of beta 2 agonists, cholinergic drugs, and adenosine triphosphate (ATP). They trigger cilia to move faster in response to elevated cytoplasmic Ca 2+ originated from intracellular sources or replenished from extracellular space. Well-known cilia-stimulatory effect of Ca 2+ ions can be abolished or even reversed by modulating the phosphodiesterase (PDE)-mediated breakdown of cyclic adenosine monophosphate (cAMP) since the overall change in ciliary beating has been dependent on the balance between Ca 2+ ions and cAMP. Moreover, in chronic respiratory diseases, high ATP levels may contribute to cAMP hydrolysis and thus to a decrease in the ciliary beat frequency (CBF). The role of PDE inhibitors in airway cilia-driven transport may help in prevention of progressive loss of pulmonary function often observed despite current therapy. Furthermore, administration of selective PDE inhibitors by inhalation lowers the risk of their systemic effects. Based on this review we may conclude that selective (PDE1, PDE4) or dual PDE inhibitors (PDE3/4) increase the intracellular level of cyclic nucleotides in airway epithelial cells and thus may be an important target in the development of new inhaled mucokinetic agents. Further research is required to provide evidence of their effectiveness and feasibility regarding their cilia-modulating properties.

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Section: Selective Pde4 Inhibitorssupporting

confidence: 86%

Section: Pde and Ciliary Motilitymentioning

confidence: 99%

Section: Pde and Ciliary Motilitymentioning

confidence: 99%

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Respiratory Cilia as a Therapeutic Target of Phosphodiesterase Inhibitors

2020

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“…As in our case, patients with status asthmaticus are usually unresponsive to β 2 -agonists, at least partly due to receptor desensitisation [4]. In experimental models of allergic asthma, enoximone has bronchodilatory and anti-inflammatory effects, yielding a biological rationale for using this compound in patients with severe asthma [8].…”

supporting

confidence: 53%

Enoximone in status asthmaticus

et al. 2020

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Bronchial asthma is a chronic disease affecting >300 million people worldwide [1]. The most severe disease manifestation is status asthmaticus, which can be unresponsive to medical therapy. Patients with severe status asthmaticus who require intubation and mechanical ventilation have mortality rates of up to 20% [2]. Airflow obstruction is often so severe that adequate decarboxylation and protective ventilation are not feasible, and extracorporeal membrane oxygenation (ECMO) support is nowadays an established treatment option as a bridge to recovery [3, 4].

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“…Despite PDE3 being present in T lymphocytes, it has a limited impact on T-cell proliferation and cytokine production (Giembycz, Corrigan, Seybold, Newton, & Barnes, 1996). gesting that PDE3 may act as a novel anti-inflammatory target in allergic airway inflammation (Beute et al, 2018). Regarding bronchodilation, a substantial body of evidence shows that PDE3 inhibitors (siguazodan, SK&F94120, and org9935) are potent relaxants in airway smooth muscle (Bernareggi, Belvisi, Patel, Barnes, & Giembycz, 1999;Nicholson et al, 1995;Torphy et al, 1993), while contrasting findings are reported regarding PDE4 inhibition in various animal models.…”

Section: Outlook and Future Perspectivesmentioning

confidence: 99%

Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

Zuo

Cattani‐Cavalieri

Musheshe

et al. 2019

British J Pharmacology

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Over the past decades, research has defined cAMP as one of the central cellular nodes in sensing and integrating multiple pathways and as a pivotal role player in lung pathophysiology. Obstructive lung disorders, such as chronic obstructive pulmonary disease (COPD), are characterized by a persistent and progressive airflow limitation and by oxidative stress from endogenous and exogenous insults. The extent of airflow obstruction depends on the relative deposition of different constituents of the extracellular matrix, a process related to epithelial‐to‐mesenchymal transition, and which subsequently results in airway fibrosis. Oxidative stress from endogenous and also from exogenous sources causes a profound worsening of COPD. Here we describe how cAMP scaffolds and their different signalosomes in different subcellular compartments may contribute to COPD. Future research will require translational studies to alleviate disease symptoms by pharmacologically targeting the cAMP scaffolds. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

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A pathophysiological role of PDE3 in allergic airway inflammation

Cited by 33 publications

References 85 publications

Respiratory Cilia as a Therapeutic Target of Phosphodiesterase Inhibitors

Respiratory Cilia as a Therapeutic Target of Phosphodiesterase Inhibitors

Enoximone in status asthmaticus

Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

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