Phosphodiesterase‐4 inhibition improves corticosteroid insensitivity in pulmonary endothelial cells under oxidative stress

Ortiz, J.L.; Milara, Javier; Serrá, Juan Antonio Monsoriu; Diego, A. De; Sanz, Celia; Cortijo, Julio

doi:10.1111/all.12055

Cited by 21 publications

(17 citation statements)

References 43 publications

(62 reference statements)

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“…Other studies have reported additive effects of cAMP elevating agents on both expression and activation of the glucocorticoid receptor (GR), including both β 2 agonists and PDE4 inhibitors (Ortiz et al. 2012; Roth et al. 2002).…”

Section: Discussionmentioning

confidence: 99%

“…PDE4 inhibitors have proven potential as anti-inflammatory drugs in chronic airway diseases. By increasing intracellular cAMP levels, PDE4 inhibitors elicit a broad spectrum of antiinflammatory effects, including the suppression of the release of mucins (Mata et al 2005), inflammatory cytokines, and other mediators (Buenestado et al 2011;Burgess et al 2006;Ouagued et al 2005), and also inhibit the actions of reactive oxygen species which are proinflammatory in nature (Brown et al 2007;de Visser et al 2011;Ortiz et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Edwards

Facchinetti

Civelli

et al. 2016

Pharmacology Res & Perspec

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Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS‐2B), we investigated the potential anti‐inflammatory effects of CHF6001 on rhinovirus (RV1B)‐induced cytokines. Cytokine mRNA was measured by real‐time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7‐point dose–response curve (1000–0.001 nmol/L) as a 1.5‐h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B‐induced IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein in a concentration‐dependent manner. Generally, CHF6001 was 13‐ to 16‐fold more potent (subnanomolar EC 50 values) than roflumilast at reducing IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV‐induced cytokines when compared with steroid or CHF6001 alone. Combined low‐dose steroid and low‐dose CHF6001 had a similar efficacy as high‐dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti‐inflammatory activity against virus‐induced inflammatory mediators and that CHF6001 is more potent than roflumilast.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Edwards

Facchinetti

Civelli

et al. 2016

Pharmacology Res & Perspec

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“…These metabolites have regulatory and homeostatic functions and participate in the complicated inflammatory processes of airway eosinophilia, edema, hypersecretion of mucus, remodeling, and AHR observed in patients with airway diseases (40,41).…”

Section: Arachidonic Acid Metabolitesmentioning

confidence: 99%

Transforming growth factor‐beta 1 pathways in inflammatory airway diseases

Yang

Zhang

Feng

et al. 2014

Allergy

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Transforming growth factor-beta 1 (TGF-b1) has been reported being involved in the remodeling and immunosuppression processes of inflammatory airway diseases; understanding the regulation of TGF-b1 is therefore a key to unravel the pathomechanisms of these diseases. This review briefly summarizes the current knowledge on the influencing factors for driving TGF-b1 and its regulatory pathways in inflammatory airway diseases and discusses possible therapeutic approaches to TGF-b1 control. The factors include smoking and oxidative stress, prostaglandins (PGs), leukotrienes (LTs), bradykinin (BK), and microRNAs (miRs). Based on the summary, new innovative treatment strategies may be developed for inflammatory airway diseases with an impaired expression of TGF-b1.The transforming growth factor-beta (TGF-b) superfamily is critically involved in embryonic development, organogenesis, and tissue homeostasis. It acts as multifunctional regulators of cell growth and differentiation and consists of more than 40 members, mainly including TGF-bs, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins, and inhibins. Between these superfamily members, there is a complex network of regulatory mechanisms (1, 2).Possessing immunomodulatory and fibrogenic characteristics, TGF-b1 is a pleiotropic and multifunctional cytokine secreted from various types of cells, such as endothelial, epithelial and smooth muscle cells, as well as fibroblasts and most immune system cells.Transforming growth factor-beta 1 regulation is unique because it is targeted to the extracellular matrix as a biologically inactive complex, which consists of a mature 25-kDa polypeptide dimer (TGF-b), a latency-associated protein (LAP), and a latent TGF-b-binding protein (LTBP). Active TGF-b is released from the latent complex that was activated via cleavage by proteases and other molecules. The activated TGF-b then becomes a ligand for TGF-b type I and II receptors, leading to receptor Smad (R-Smad) phosphorylation, which subsequently binds to the common-partner Smad (co-Smad), and becoming Smad complexes. The Smad complexes translocate into the nucleus and combine with several transcription factors, thereby becoming a transcriptional active complex that activates target genes transcription. In Abbreviations AHR, airway hyper-responsiveness; BAMBI, BMP and activin membrane-bound inhibitor; BK, bradykinin; BMP, bone morphogenetic protein; CCL2/MCP-1, chemokine (CC motif) ligand 2/monocyte chemotactic protein-1; COPD, chronic obstructive pulmonary disease; CRS, chronic rhinosinusitis; CysLT, cysteinyl leukotriene; FoxP3, forkhead box P3; LAP, latency-associated protein; LTBP, latent TGF-b-binding protein; miR, microRNA; PG, prostaglandin; RORc, RAR-related orphan receptor C; TGF-b1, transforming growth factor-beta 1.Allergy 69 (2014) 699-707

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“…Another study [13] showed that cigarette smoke inhibited HDAC activity in human pulmonary artery endothelial cells. In a study of 49 COPD patients and 42 healthy controls, HDAC2 mRNA and protein expression was found to correlate with development and prognosis of COPD, suggesting it could be used as a biomarker.…”

Section: Expression Of Histone Deacetylases Enzymes Chronic Respiratomentioning

confidence: 99%

Histone deacetylases and their inhibitors

Royce

Karagiannis

2014

Current Opinion in Allergy &Amp; Clinical Immunology

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Important developments have been made in the understanding of histone deacetylase expression in normal and diseased airways and pulmonary tissue as well as effects of histone deacetylase inhibitors on structural and inflammatory cells in the lung, including cell proliferation, differentiation and apoptosis and senescence. Many of these discoveries may have implications in addressing airway inflammation, airway remodeling and airway hyperresponsiveness in asthma.

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Phosphodiesterase‐4 inhibition improves corticosteroid insensitivity in pulmonary endothelial cells under oxidative stress

Abstract: Combination of rolipram and dexamethasone shows additive properties in HPAECs under glucocorticoid insensitive conditions. These results may be of potential value in future anti-inflammatory therapies using combination of PDE4 inhibitors and glucocorticoids.

Cited by 21 publications

References 43 publications

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Transforming growth factor‐beta 1 pathways in inflammatory airway diseases

Histone deacetylases and their inhibitors

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