The PDE4 Inhibitor Tanimilast Restrains the Tissue-Damaging Properties of Human Neutrophils (original) (raw)
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Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases
Memórias do Instituto Oswaldo Cruz, 2005
Phosphodiesterases (PDEs) are responsible for the breakdown of intracellular cyclic nucleotides, from which PDE4 are the major cyclic AMP metabolizing isoenzymes found in inflammatory and immune cells. This generated greatest interest on PDE4 as a potential target to treat lung inflammatory diseases. For example, cigarette smokeinduced neutrophilia in BAL was dose and time dependently reduced by cilomilast. Beside the undesired side effects associated with the first generation of PDE4 inhibitors, the second generation of selective inhibitors such as cilomilast and roflumilast showed clinical efficacy in asthma and chronic obstrutive pulmonary diseases trials, thus re-enhancing the interest on these classes of compounds. However, the ability of PDE4 inhibitors to prevent or modulate the airway remodelling remains relatively unexplored. We demonstrated that selective PDE4 inhibitor RP 73-401 reduced matrix metalloproteinase (MMP)-9 activity and TGF-β1 release during LPS-induced lung injury in mice and that CI-1044 inhibited the production of MMP-1 and MMP-2 from human lung fibroblasts stimulated by pro-inflammatory cytokines. Since inflammatory diseases of the bronchial airways are associated with destruction of normal tissue structure, our data suggest a therapeutic benefit for PDE4 inhibitors in tissue remodelling associated with chronic lung diseases.
American Journal of Respiratory and Critical Care Medicine, 2003
Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8ϩ and CD4ϩ T-lymphocyte subsets, and CD68ϩ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-␣ were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV 1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8ϩ (p ϭ 0.001; ANOVA) and CD68ϩ cells (p Ͻ 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8ϩ (48% p Ͻ 0.01) and CD68ϩ (47% p ϭ 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.
Pulmonary Pharmacology & Therapeutics, 2003
Selective inhibitors of phosphodiesterase-4 (PDE4) inhibit the hydrolysis of intracellular cAMP, which may result in bronchodilation and suppression of inflammation. We examined the effect of 1 week treatment with BAY 19-8004 (5 mg once daily), a novel orally administered PDE4 inhibitor, on trough FEV 1 and markers of inflammation in induced sputum in patients with asthma or chronic obstructive pulmonary disease (COPD). Seven patients with asthma (mean [SD] FEV 1 69.5 [9.3]% predicted; reversibility in FEV 1 26.2 [10.1]%; all non-smokers) and 11 patients with COPD (FEV 1 58.6 [8.3]% predicted; reversibility in FEV 1 6.5 [4.7]%; median [range] 44 [21 -90] pack years of smoking) were included in this randomized, double-blind, placebo-controlled trial. FEV 1 was measured before and after 1 week of treatment; sputum was induced by 4.5% saline inhalation on the last day of treatment. FEV 1 did not improve during either treatment in both patient groups ðp . 0:2Þ: Sputum cell counts were not different following placebo and BAY 19-8004 treatment in asthma and COPD patients ðp . 0:2Þ: However, only in patients with COPD, small but significant reductions in sputum levels of albumin and eosinophil cationic protein were observed ðp , 0:05Þ: In conclusion, 1 week of treatment with the selective PDE4 inhibitor BAY 19-8004 does not affect FEV 1 and sputum cell numbers in patients with asthma or COPD. However, such treatment does seem to reduce levels of albumin and eosinophil cationic protein in sputum samples obtained from patients with COPD. q
Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD
Respiratory Research, 2019
Background: CHF6001 is a novel inhaled phosphodiesterase-4 inhibitor. This Phase IIa study assessed the effects of CHF6001 on markers of inflammation in induced sputum and blood in patients with chronic obstructive pulmonary disease (COPD). Methods: This was a multicentre, three-period (each 32 days), three-way, placebo-controlled, double-blind, complete-block crossover study. Eligible patients had COPD, chronic bronchitis, and were receiving inhaled triple therapy for ≥2 months. Patients received CHF6001 800 or 1600 μg, or matching placebo twice daily via multi-dose dry-powder inhaler (NEXThaler). Induced sputum was collected pre-dose on Day 1, and post-dose on Days 20, 26 and 32. Blood was sampled pre-dose on Day 1, and pre-and post-dose on Day 32. Results: Of 61 randomised patients, 54 (88.5%) completed the study. There were no significant differences between groups for overall sputum cell count, or absolute numbers of neutrophils, eosinophils or lymphocytes. CHF6001 800 μg significantly decreased the absolute number and percentage of macrophages vs placebo. In sputum, compared with placebo both CHF6001 doses significantly decreased leukotriene B4, C-X-C motif chemokine ligand 8, macrophage inflammatory protein 1β, matrix metalloproteinase 9, and tumour necrosis factor α (TNFα). In blood, both CHF6001 doses significantly decreased serum surfactant protein D vs placebo. CHF6001 1600 μg significantly decreased TNFα ex-vivo (after incubation with lipopolysaccharide). Conclusion: The data from this study show that CHF6001 inhaled twice daily has anti-inflammatory effects in the lungs of patients with COPD already treated with triple inhaled therapy. Trial registration: The study is registered on ClinicalTrials.gov (NCT03004417).
Phosphodiesterase (PDE) 7 in inflammatory cells from patients with asthma and COPD
Pulmonary Pharmacology & Therapeutics, 2007
In inflammatory cells, the low K m cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) 4 subtype is predominant in terms of expression and function, although more recently it has been suggested that PDE 7 may also play a role in regulating inflammatory cell activity. In the present study, PDE 4 and PDE 7 subtype messenger ribonucleic acid (mRNA) transcripts in CD4 and CD8 lymphocytes from healthy (n ¼ 10) and asthmatic (n ¼ 10) subjects and polymorphonuclear neutrophils (PMNs) and CD8 lymphocytes obtained from healthy (n ¼ 10) and chronic obstructive pulmonary disease (COPD) (n ¼ 7) subjects were identified and quantified. PDE 4A, PDE 4B, PDE 4D and PDE 7A mRNA were present in similar quantities in both CD4 and CD8 lymphocytes obtained from healthy and asthmatic subjects and in CD8 lymphocytes obtained from healthy and COPD subjects. Expression of PDE 4C and PDE 7B mRNA was also observed, although transcript levels were low and variable between individuals. In addition, the effects of selective PDE 7 inhibition on both phytohaemagluttinin (PHA)-induced human peripheral blood mixed mononuclear cell (HPBMNC) proliferation and fMLP-induced neutrophil elastase (NE) release were studied. HPBMNC and human neutrophils, isolated from the venous blood of healthy volunteers (n ¼ 6) were treated with either a novel selective PDE 7 inhibitor PF 0332040 alone or in combination with rolipram. Proliferation of HPBMNC was stimulated by PHA (2 mg ml À1 ) and assessed by [ 3 H]-thymidine incorporation, while fMLP-induced (100 nM) NE release was determined using a chromogenic substrate. Both rolipram (0.003-10 mM) and PF 0332040 (0.003-10 mM) significantly inhibited PHA-stimulated proliferation of HPBMNC ( ÃÃ Po0:01). Co-administration of rolipram (0.3-10 mM) and PF 0332040 (0.003-10 mM) significantly increased the degree of inhibition observed, compared to when either drug was administered alone ( ÃÃ Po0:01). PF 0332040 (0.003-10 mM) had no inhibitory effect on NE release from human peripheral blood neutrophils stimulated with fMLP (100 nM), while rolipram (0.003-10 mM) significantly inhibited neutrophil degranulation ( ÃÃ Po0:01). These findings suggest no evidence of altered PDE 4 or PDE 7 mRNA transcript levels in inflammatory cells isolated from the peripheral venous blood of mild asymptomatic asthmatic subjects or stable COPD subjects, however, inhibition of PDE 7 may influence mononuclear cell function. r
Pulmonary pharmacology & therapeutics, 2005
Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor alpha (TNF-alpha) plays a central role as a pro-inflammatory cytokine in COPD. TNF-alpha release is markedly inhibited by phosphodiesterase type 4 (PDE4) inhibitors that have proven efficacious in COPD clinical trials. The aim of this study was to compare the in vitro activities of the novel selective PDE4 inhibitors CI-1044 compared to well-known PDE4 inhibitors, rolipram and cilomilast, and to the glucocorticoid dexamethasone at reducing lipopolysaccharide (LPS)-induced TNF-alpha release in whole blood from COPD patients and healthy subjects. In the whole blood from COPD patients pre-incubation with PDE4 inhibitors or dexamethasone resulted in a dose-dependent inhibition of LPS-induced TNF-alpha release with IC(50) values of 1.3+/-0.7, 2.8+/-0.9 microM, higher to 10 microM and lesser than 0.03 microM for CI-104...
Thorax, 2007
Background: Roflumilast is a targeted oral once-daily administered phosphodiesterase 4 (PDE4) inhibitor with clinical efficacy in chronic obstructive pulmonary disease (COPD). Results from in vitro studies with roflumilast indicate that it has anti-inflammatory properties that may be applicable for the treatment of COPD. Methods: In a crossover study, 38 patients with COPD (mean (SD) age 63.1 (7.0) years, post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 61.0 (12.6)% predicted) received 500 mg roflumilast or placebo once daily for 4 weeks. Induced sputum samples were collected before and after 2 and 4 weeks of treatment. Differential and absolute cell counts were determined in whole sputum samples. Markers of inflammation were determined in sputum supernatants and blood. Spirometry was performed weekly. Results: Roflumilast significantly reduced the absolute number of neutrophils and eosinophils/g sputum compared with placebo by 35.5% (95% CI 15.6% to 50.7%; p = 0.002) and 50.0% (95% CI 26.8% to 65.8%; p,0.001), respectively. The relative proportion of sputum neutrophils and eosinophils was not affected by treatment (p.0.05). Levels of soluble interleukin-8, neutrophil elastase, eosinophil cationic protein and a 2macroglobulin in sputum and the release of tumour necrosis factor a from blood cells were significantly reduced by roflumilast compared with placebo treatment (p,0.05 for all). Post-bronchodilator FEV 1 improved significantly during roflumilast compared with placebo treatment with a mean difference between treatments of 68.7 ml (95% CI 12.9 to 124.5; p = 0.018). Conclusion: PDE4 inhibition by roflumilast treatment for 4 weeks reduced the number of neutrophils and eosinophils, as well as soluble markers of neutrophilic and eosinophilic inflammatory activity in induced sputum samples of patients with COPD. This anti-inflammatory effect may in part explain the concomitant improvement in post-bronchodilator FEV 1 .
Scientific Reports, 2022
Non-T2 severe asthma and chronic obstructive pulmonary disease (COPD) are airway chronic inflammatory disorders with a poor response to corticosteroids. LAS194046, a novel pan-Janus kinase (JAK) inhibitor, shows inhibitory effects on T2 allergic lung inflammation in rats. In this work we analyze the effects of LAS194046, fluticasone propionate and their combination in neutrophils from non-T2 severe asthma and COPD patients in vitro. Neutrophils from 23 healthy subjects, 23 COPD and 21 non-T2 severe asthma patients were incubated with LAS194046 (0.01 nM-1 µM), fluticasone propionate (0.1 nM-1 µM) or their combination and stimulated with lipopolysaccharide (LPS 1 µM). LAS194046 shows similar maximal % inhibition and potency inhibiting IL-8, MMP-9 and superoxide anion release in neutrophils from healthy, COPD and asthma. Fluticasone propionate suppresses mediator release only in neutrophils from healthy patients. The combination of LAS194046 with fluticasone propionate shows synergistic anti-inflammatory and anti-oxidant effects. The mechanisms involved in the synergistic effects of this combination include the increase of MKP1 expression, decrease of PI3Kδ, the induction of glucocorticoid response element and the decrease of ERK1/2, P38 and JAK2/STAT3 phosphorylation compared with monotherapies. In summary, LAS194046 shows anti-inflammatory effects in neutrophils from COPD and severe non-T2 asthma patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate. Chronic airway inflammation is a key feature in severe asthma and chronic obstructive pulmonary disease (COPD), which is poorly controlled by inhaled or systemic corticosteroids 1. Searching for new anti-inflammatory therapies to improve chronic inflammation and to improve the anti-inflammatory effects of corticosteroids has been a constant in the last decades of asthma and COPD pharmacologic research. In this regard, the first introduction of anti-leukotrienes, improved the inflammatory profile of mild allergic asthma, but not in severe asthma. The recent introduction of biologic treatments, such as the anti-IgE, anti-IL-5 and anti-IL-4Rα (IL-4/ IL-13) monoclonal antibodies have change the management of severe asthma. However, biologic treatments show efficacy in T2 eosinophilic severe asthma (> 300 eosinophils/µL) patients 2 , improving inflammatory profile, lung function, symptoms and quality of life, although the long term clinical remission on treatment is reached only in 14-28% of patients with this asthma phenotype 3 In contrast, non-T2 inflammatory asthma phenotypes, represented by mixed or pure forms of T1/T17 or neutrophilic inflammation shows less response to inhaled/ systemic corticosteroids and biologic treatments, representing around 30% of severe asthma phenotypes with a poor prognosis 4,5. Neutrophilic airway inflammation is present in individuals who had generally adult-onset and severely obstructed (and incompletely reversible) asthma and the highest-intensity healthcare usage and systemic corticosteroid use 6 which shares similarities with COPD (namely asthma-COPD overlap). Similar immunobiology profile has been observed in mild-severe COPD patients showing increased number and activated neutrophils in sputum and blood, characterized by an elevated oxidative stress, matrix metalloproteinases,
Role of phosphodiesterase-4 inhibitors in chronic obstructive pulmonary disease
The Korean Journal of Internal Medicine
Phosphodiesterase-4 inhibitors (PDE4Is) are potent anti-inf lammatory agents and roflumilast has been used to prevent acute exacerbation of chronic obstructive pulmonary disease (COPD). Roflumilast decreases neutrophil migration, restores cystic fibrosis transmembrane conductance regulator activity, and recovers glucocorticoid effects. A forced expiratory volume in 1 second of < 50%, a chronic bronchitis phenotype, high blood eosinophil levels, and a history of hospitalization are biomarkers for predicting responses to roflumilast. Adverse effects are common in clinical practice. An inhaled PDE4I has recently been developed and is under clinical trial. CHF6001 and RPL554 exhibit promise and may be future treatment options for COPD.