PDE4 inhibitors as new anti-inflammatory drugs: Effects on cell trafficking and cell adhesion molecules expression

Sanz, María-Jesús; Cortijo, Julio; Morcillo, Esteban J.

doi:10.1016/j.pharmthera.2004.12.001

Cited by 96 publications

(82 citation statements)

References 317 publications

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“…PDEs, including PDE4, break down cAMP and cGMP and play a key role in inflammatory and immune responses (44). PDE4s are the major isozymes highly expressed in immune cells, airway epithelial cells, and smooth muscle cells (17).…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

Forkuo

Kim

Thanawala

et al. 2016

Am J Respir Cell Mol Biol

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Mice lacking the endogenous b 2 -adrenoceptor (b 2 AR) agonist epinephrine (phenylethanolamine N-methyltransferase [PNMT]-knockout mice) are resistant to developing an "asthma-like" phenotype in an ovalbumin sensitization and challenge (Ova S/C) model, and chronic administration of b 2 AR agonists to PNMT-KO mice restores the phenotype. Based on these and other studies showing differential effects of various b 2 AR ligands on the asthma phenotype, we have speculated that the permissive effect of endogenous epinephrine and exogenous b 2 AR agonists on allergic lung inflammation can be explained by qualitative b 2 AR signaling. The b 2 AR can signal through at least two pathways: the canonical Gas-cAMP pathway and a b-arrestin-dependent pathway. Previous studies suggest that b-arrestin-2 is required for allergic lung inflammation. On the other hand, cell-based assays suggest antiinflammatory effects of Gas-cAMP signaling. This study was designed to test whether the in vitro antiinflammatory effects of phosphodiesterase 4 inhibitors, known to increase intracellular cAMP in multiple airway cell types, attenuate the asthma-like phenotype produced by the b 2 AR agonists formoterol and salmeterol in vivo in PNMT-KO mice, based on the hypothesis that skewing b 2 AR signaling toward Gas-cAMP pathway is beneficial. Airway inflammatory cells, epithelial mucus production, and airway hyperresponsiveness were quantified. In Ova S/C PNMT-KO mice, formoterol and salmeterol restored the asthma-like phenotype comparable to Ova S/C wild-type mice. However, coadministration of either roflumilast or rolipram attenuated this formoterol-or salmeterol-driven phenotype in Ova S/C PNMT-KO. These findings suggest that amplification of b 2 AR-mediated cAMP by phosphodiesterase 4 inhibitors attenuates the asthma-like phenotype promoted by b-agonists.

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Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

Forkuo

Kim

Thanawala

et al. 2016

Am J Respir Cell Mol Biol

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“…Rolipram is the prototypical PDE4 selective inhibitor. PDEA4 enzyme is the main cAMP-metabolizing enzyme in immune and inflammatory cells, airway smooth muscle, and pulmonary nerves; its inhibition suppresses the recruitment and activation of several inflammatory cells (neutrophils, CD8 T cells, and macrophages) known to have a crucial role in the pathophysiological processes of bronchopulmonary dysplasia (Sanz et al, 2005;Hayes et al, 2010). In this context, we chose to test this new treatment in a previously described model of antenatal infection with subsequent impaired alveolarization in the rabbit (Gras-Le Guen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Among the 11 families of PDEs, selective inhibition of PDE4 increases intracellular cAMP levels, particularly in inflammatory cells (T and B lymphocytes and polymorphonuclear neutrophils), respiratory epithelial cells, and endothelial cells (Torphy, 1998), thus modulating cellular trafficking and cytokine and chemokine responses (Sanz et al, 2005;Bender and Beavo, 2006). Moreover, inhibition of PDE4 limits interstitial fibrosis and enhances muscular relaxation in airways (Kohyama et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Antenatal Phosphodiesterase 4 Inhibition Restores Postnatal Growth and Pulmonary Development in a Model of Chorioamnionitis in Rabbits

Homer¹,

Launay²,

Joram³

et al. 2011

J Pharmacol Exp Ther

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Chorioamnionitis is implicated in the pathophysiology of bronchopulmonary disease, and the associated inflammatory response is responsible for adverse effects on alveolar development. The aim of this work was to analyze the effects of a phosphodiesterase 4 (PDE4)-selective inhibitor, rolipram (a modulator of the inflammatory response), in an experimental model of chorioamnionitis on pulmonary development and on the processes of infection and inflammation. Rabbit mothers were assigned to four groups: 1) saline serum inoculation (controls); 2) Escherichia coli intrauterine inoculation (Cϩ); 3) rolipram infusion (Rϩ); and 4) E. coli inoculation ϩ rolipram infusion (CϩRϩ). High rates of morbility and mortality were noticed in mothers and pups (5 of 13 pregnant rabbits in groups with rolipram). Alveolar development, inflammation, and infection were analyzed in pups at day 0 and day 5. At day 0, in the context of chorioamnionitis, rolipram significantly decreased birth weight (p Ͻ 0.01) relative to that of controls (p Ͻ 0.05). At day 5, weight normalized in group CϩRϩ but not in group Cϩ relative to controls (p Ͻ 0.001); moreover, alveolar airspace volume was preserved in group CϩRϩ but not in group Cϩ (p Ͻ 0.05). Interstitial volume decreased in group Cϩ versus controls (p Ͻ 0.05) but was preserved in group CϩRϩ. Specific alveolar area was not significantly modified by rolipram. No significant difference was found concerning bronchoalveolar lavage cellularity, and all blood cultures remained sterile. In this model of impaired alveologenesis, rolipram significantly preserved specific alveolar density. However, PDE4 inhibition induced antenatal fetal demise and growth retardation.

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“…Nötrofil ve eozinofil infiltrasyonunu inhibe ettiği, aktive T-helper hücreleri, hava yolu epitel hücreleri, bazofil ve makrofajlardan sitokin salınımını baskıladığı bulunmuştur (20,21). Ayrıca, tümör nekroz faktorü-alfa (TNF-α) ve interlökin-1beta (IL-1β) etkisiyle bronş düz kas hücrelerinden granülosit makrofaj koloni stimüle edici faktör salınımını baskılamaktadır (22).…”

Section: Fde-4 Inhibitörlerinin Koah'da Etkinlik Ve Tolerabilitesini unclassified

A new alternative treatment in COPD: phosphodiesterase-4 inhibitors

Sezgı

Şenyiğit²

2011

Tuberk Toraks

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ÖZET KOAH'da yeni tedavi seçeneği: Fosfodiesteraz-4 inhibitörleri Kronik obstrüktif akciğer hastalığı (KOAH) ilerleyici hava akımı kısıtlanması ile karakterize, zararlı gaz ve tozlara karşı abartılı inflamatuvar yanıtla ortaya çıkan bir hastalıktır. İnflamatuvar hücrelerin aktivasyonunu engelleyen oral fosfodiesteraz-4 (FDE-4) inhibitörleri son yıllarda KOAH tedavisinde yeni bir yaklaşım olarak denenmektedir. Çalışmalar FDE-4 inhibitörlerinin orta-ağır KOAH hastalarının semptomlarını, solunum fonksiyonlarını ve yaşam kalitesini düzelttiğini, akut atak sayısını azalttığını, bronşlardaki inflamasyonu baskıladığını göstermiştir. Ancak bu ilaçlar bulantı, ishal ve baş ağrısı gibi istenmeyen yan etkilere neden olmaktadır. Bu derlemede özellikle "Food and Drug Administration (FDA)" onayı almış, yeni "The Global Initiative for Chronic Obstructive Lung Disease (GOLD)" rehberinde ağır KOAH tedavisine dahil edilmiş selektif bir fosfodiesteraz inhibitörü olan roflumilast tartışılmıştır.

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PDE4 inhibitors as new anti-inflammatory drugs: Effects on cell trafficking and cell adhesion molecules expression

Cited by 96 publications

References 317 publications

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

Antenatal Phosphodiesterase 4 Inhibition Restores Postnatal Growth and Pulmonary Development in a Model of Chorioamnionitis in Rabbits

A new alternative treatment in COPD: phosphodiesterase-4 inhibitors

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PDE4 inhibitors as new anti-inflammatory drugs: Effects on cell trafficking and cell adhesion molecules expression

Cited by 96 publications

References 317 publications

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

Antenatal Phosphodiesterase 4 Inhibition Restores Postnatal Growth and Pulmonary Development in a Model of Chorioamnionitis in Rabbits

A new alternative treatment in COPD: phosphodiesterase-4 inhibitors

Contact Info

Product

Resources

About

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice