Phosphodiesterase 4 inhibitors delay human eosinophil and neutrophil apoptosis in the absence and presence of salbutamol

Parkkonen, Jouni; Hasala, Hannele; Moilanen, Eeva; Giembycz, Mark A.; Kankaanranta, Hannu

doi:10.1016/j.pupt.2007.11.003

Cited by 20 publications

(15 citation statements)

References 34 publications

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“…tor agonists (Parkkonen et al, 2007). However, to what extent these findings translate into the clinic, particularly, if combined with bronchodilator drugs, remains to be established.…”

Section: Pde4 Inhibitors and Respiratory Disease D Spinamentioning

confidence: 99%

“…It is unlikely that the plasma concentrations required to produce this purported proinflammatory effect could be achieved even with chronic dosing. Similarly, another study has shown that PDE4 inhibitors, at concentrations that are pharmacologically relevant, delay apoptosis of neutrophils and eosinophils, an effect that increased when combined with β2‐adrenoceptor agonists ( Parkkonen et al ., 2007 ). However, to what extent these findings translate into the clinic, particularly, if combined with bronchodilator drugs, remains to be established.…”

Section: Introductionmentioning

confidence: 99%

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PDE4 inhibitors: current status

Spina

2008

British J Pharmacology

304

227

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Phosphodiesterase4 inhibitors are currently under development for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease. The rationale for the development of this drug class stems from our understanding of the role of PDE4 in suppressing the function of a range of inflammatory and resident cells thought to contribute toward the pathogenesis of these diseases. Similarly, numerous preclinical in vivo studies have shown that PDE4 inhibitors suppress characteristic features of these diseases, namely, cell recruitment, activation of inflammatory cells and physiological changes in lung function in response to a range of insults to the airways. These potentially beneficial actions of PDE4 inhibitors have been successfully translated in phase II and III clinical trials with roflumilast and cilomilast. However, dose limiting side effects of nausea, diarrhoea and headache have tempered the enthusiasm of this drug class for the treatment of these respiratory diseases. A number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects, including delivery via the inhaled route, and/or development of non-emetic PDE4 inhibitors and mixed PDE inhibitors.

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“…tor agonists (Parkkonen et al, 2007). However, to what extent these findings translate into the clinic, particularly, if combined with bronchodilator drugs, remains to be established.…”

Section: Pde4 Inhibitors and Respiratory Disease D Spinamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PDE4 inhibitors: current status

Spina

2008

British J Pharmacology

304

227

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“…For example, the roles of β-receptor, cAMP, protein kinase A and Ca 2+ -activated K + -channels are not known. Some other cAMP-increasing agents such as forskolin and prostaglandin E 2 have been reported to prolong eosinophil survival [13][14][15][16] and we recently reported that a combination of a phosphodiesterase 4 inhibitor with a β 2 -agonist also prolonged eosinophil survival [17]. This suggests that a cAMP-…”

Section: Introductionmentioning

confidence: 81%

“…However, studies investigating the mechanism of the inhibitory action of β 2 -agonists on eosinophil apoptosis are lacking. Previously, we have shown that inhibition of cAMP hydrolysing phosphodiesterases 3 or 4 by pharmacological inhibitors such as cilostazol and rolipram is able to enhance eosinophil survival in the absence and presence of salbutamol [17]. Furthermore, some cAMP elevating agents,…”

Section: Discussionmentioning

confidence: 99%

Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism

Kankaanranta¹,

Parkkonen²,

Ilmarinen³

et al. 2011

Pulmonary Pharmacology & Therapeutics

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Eosinophils play a major role in asthma. One described mechanism leading to the impaired clearance of these cells from the lung is the delay in their programmed cell death (apoptosis). β 2 -adrenoceptor agonists have been shown to prolong survival and delay apoptosis of eosinophils. The aim of the present study was to evaluate the mechanisms, especially the role of cAMP pathway, in the prolongation of human eosinophil survival by a selective β 2 -agonist salbutamol.Isolated human peripheral blood eosinophils were cultured in the absence or presence of a β 2 -agonist salbutamol and the indicated antagonists/inhibitors under sterile conditions. Apoptosis was measured by using the relative DNA fragmentation assay and Annexin-V binding.Salbutamol prolonged survival of human eosinophils and it was inhibited by a β-receptor antagonist propranolol and mimicked by cell-permeant cAMP analogues dibutyryl-and 8-bromo-cAMP. Pharmacological inhibitors of adenylyl cyclase (SQ-22,536) and protein kinase A (Rp-8-CPT-cAMPS) antagonized the effects of salbutamol. The survival-prolonging action of salbutamol was potentiated by a phosphodiesterase inhibitor rolipram (EC 50 for the salbutamol effect was 13.6 ± 4.0 and 8.1 ± 3.1 nM in the absence and presence of rolipram, respectively; P=0.0142, n=10).In contrast, inhibition of Ca 2+ -activated K + -channels by apamin, charybdotoxin, iberiotoxin or paxilline did not affect the ability of salbutamol to prolong eosinophil survival.Taken together, the present results suggest that salbutamol at clinically relevant concentrations decreases apoptosis in human eosinophils by activating the cannonical β 2 -receptor-adenylyl cyclase-cAMP-protein kinase A pathway.

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“…, 1999). In addition, they have also been shown to delay spontaneous human eosinophil apoptosis (Parkkonen et al. , 2008).…”

Section: In Vitro Effects Of Pde3 and Pde4 Inhibitors Along With Evidmentioning

confidence: 99%

Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease

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Press

2009

British J Pharmacology

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Phosphodiesterase (PDE)4, and to a lesser extent, PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for diseases including chronic obstructive pulmonary disease. Indeed, ibudilast and theophylline are utilized clinically, and roflumilast is in late-stage clinical development. Unfortunately, however many PDE4 and dual PDE3/4 inhibitors have failed in early development due to low therapeutic ratios. The majority of these compounds are however orally administered and non-selective for either PDE3(A, B) or PDE4(A, B, C, D) subtypes. Developing an inhaled dual PDE3/4 inhibitor with subtype specificity may represent one strategy to improve the therapeutic index. Indeed combined inhibition of PDE3 and PDE4 inhibitor has additive and synergistic anti-inflammatory and bronchodilatory effects versus inhibition of either PDE3 or PDE4 alone. Given that synergy has been seen in terms of efficacy end points, an obvious concern is that synergy may also be observed in side effects. Interestingly, however, no synergy or additive effects with a combination of a PDE3 and PDE4 inhibitor in a cardiomyocyte assay were observed. This review will summarize the rationale for developing an inhaled dual PDE3/4 inhibitor, as a treatment for chronic obstructive pulmonary disease together with recent advances in trying to understand the pathogenesis of PDE inhibitor-induced mesenteric vasculitis (a key potential dose-limiting side effect of these agents), highlighting potential early and sensitive predictive biomarkers.

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Phosphodiesterase 4 inhibitors delay human eosinophil and neutrophil apoptosis in the absence and presence of salbutamol

Cited by 20 publications

References 34 publications

PDE4 inhibitors: current status

PDE4 inhibitors: current status

Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism

Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease

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