Comparison of fluticasone, roflumilast and tiotropium in a model of influenza-induced acute COPD exacerbation
0
Citation
0
Reference
20
Related Paper
Abstract:
Background : Exacerbations of COPD are associated with increased risk of mortality. One major trigger of COPD exacerbations are influenza virus-induced respiratory tract infections. Aim : To compare the efficacy of the corticosteroid fluticasone to treatment with the PDE4 inhibitor roflumilast, and the long acting anticholinergic tiotropium in a COPD mouse model of acute virus-induced exacerbation. Methods : BALB/c mice were exposed to cigarette smoke (CS) for 2 weeks and infected with Influenza A H1N1 on day 8. In parallel to CS exposure, mice were treated with fluticasone, roflumilast or tiotropium. Mice were sacrificed on day 12 and pulmonary cell infiltration, cytokines in lung homogenate, lung function and viral replication were assessed. Results : Treatment with fluticasone showed that virus-induced neutrophilia was not only steroid insensitive, but steroid treatment lead to a worsening of health status, a more rapid and severe loss of body weight, an increase in pro-inflammatory cytokine release (IL-6, IFN-γ, IL-10 and KC), a decline in lung function and an increased viral load. Treatment with roflumilast reduced IFN-γ, IL-6, KC, and IL-10, but had only modest effects on cellular influx. Tiotropium was the only compound tested that did not only reduce IFN-γ, IL-6 and IL-10 but also significantly attenuated pulmonary cellular influx of neutrophils and macrophages. Conclusion : Our data demonstrate that in this in vivo model of Influenza-induced exacerbation fluticasone worsens health status. In contrast, treatment with roflumilast and tiotropium reduces release of pro-inflammatory cytokines. Furthermore, tiotropium efficiently reduces inflammatory cell infiltration.Keywords:
Fluticasone
Roflumilast
Cite
Background: Asthma is characterized by airway inflammation and remodeling. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor that has anti-inflammatory effect in chronic obstructive pulmonary disease (COPD). However, little is known regarding the effect of roflumilast in chronic asthma. This study is aimed to evaluate the effects of roflumilast on airway inflammation and remodelling in a murine model of chronic asthma. Methods: Female BALB/c mice, 6 weeks of age, were used. We developed a mouse model of airway remodeling in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Roflumilast was administered orally starting on the 38th and 5 days a week thereafter for 3 months during the intranasal OVA challenge. A lung fibroblast cell line was used in the proliferation assay. Results: Compared with control mice, mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, airway hyperresponsiveness (AHR), and exhibited features of airway remodeling. Administration of roflumilast significantly inhibited eosinophilic inflammation and AHR. The levels of interleukin (IL)-4, IL-5, and IL-13 in the bronchoalveolar lavage (BAL) fluids were significantly lower in the roflumilast group. The level of hydroxyproline was also significantly lower in the roflumilast group. In vitro, roflumilast significantly inhibited stem cell factor (SCF) induced cell proliferation of fibroblasts. Conclusions: These results suggest that roflumilast administration modulates the airway inflammation, AHR, and airway remodeling associated with chronic allergen challenge.
Roflumilast
Cite
Citations (0)
Background: A major cause for severe asthma exacerbations are viral infections. Asthma exacerbations are characterized by a sudden decrease in lung function associated with increased inflammation in the lung. In severe cases exacerbations cannot be sufficiently controlled by using inhaled or oral corticosteroids. Aim: Investigate the anti-inflammatory and broncho-protective effects of the selective PDE4 inhibitor Roflumilast and the corticosteroids Dexamethasone and Fluticasone in a murine influenza-induced asthma exacerbation model. Methods: BALB/c mice were sensitized with ovalbumin on day 0, 14 and 21 followed by two challenges with ovalbumin aerosol on day 26 and 27. The infection with Influenza A virus was performed intranasally on day 25. Roflumilast, Dexamethasone or Fluticasone were given either orally or intratracheally on day 25, 26 and 27. Mice were analysed on day 28. Results: All three treatments significantly reduced the numbers of macrophages and eosinophils and Th2 cytokine levels in the airways. However, only Roflumilast attenuated pulmonary neutrophilic cell influx, KC concentrations and airway hyperresponsiveness (AHR). Conclusion: In this murine model of an acute asthma exacerbation, steroid treatment had no impact on AHR or neutrophil numbers, parameters believed to be important in human asthma exacerbations. In contrast, Roflumilast reduced both parameters. These pre-clinical data suggest that in patients where asthma exacerbations cannot be controlled by an inhaled or oral corticosteroid, a PDE4 inhibitor like Roflumilast may help to reduce symptoms and the frequency of exacerbations.
Fluticasone
Roflumilast
Cite
Citations (1)
Tiotropium bromide
Cite
Citations (35)
Rhinovirus
Fluticasone propionate
Fluticasone
Cite
Citations (15)
Roflumilast is a selective phosphodiesterase-4 inhibitor that has anti-inflammatory effect in chronic obstructive pulmonary disease. However, little is known regarding the effect of roflumilast in chronic asthma. This study is aimed to evaluate the effects of roflumilast on airway inflammation and remodeling in a murine model of chronic asthma. Female BALB/c mice, 6 weeks of age, were used. We developed a mouse model of airway remodeling in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Roflumilast was administered orally starting on the 38th day and 5 days a week thereafter for 3 months during the intranasal OVA challenge. A lung fibroblast cell line was used in the proliferation assay. Compared with control mice, mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, airway hyperresponsiveness (AHR), and exhibited features of airway remodeling. Administration of roflumilast significantly inhibited eosinophilic inflammation and AHR. The levels of interleukin (IL)-4, IL-5, and IL-13 in the bronchoalveolar lavage (BAL) fluids were significantly lower in the roflumilast group. The level of hydroxyproline was also significantly lower in the roflumilast group. In vitro, roflumilast significantly inhibited stem cell factor (SCF) induced cell proliferation of fibroblasts. SCF concentration and mRNA expression also significantly decreased with roflumilast treatment. These results suggest that roflumilast administration modulates the airway inflammation, AHR, and airway remodeling associated with chronic allergen challenge. The beneficial effects from roflumilast may be related with SCF/c-kit pathway.
Roflumilast
Cite
Citations (0)
We previously demonstrated increased expression of programmed cell death 5 (PDCD5) in asthmatic patients and ovalbumin-induced allergic asthma. International guidelines (GINA 2019) have included the use of tiotropium bromide for chronic treatment of the most severe and frequently exacerbated asthma in patients ≥6 years old, who do not have good response to inhaled corticosteroids.To explore the role of tiotropium and its effect on PDCD5 level in a mouse model of chronic asthma.We divided 12 female mice into 2 groups: untreated asthma (n = 6) and tiotropium-treated asthma (n = 6). The impact of tiotropium was assessed by histology of lung tissue and morphometry. Pulmonary function was tested by using pressure sensors. The number of cells in bronchoalveolar lavage fluid (BALF) was detected. Levels of PDCD5, active caspase-3, and muscarinic acetylcholine receptors M2 (ChRM2) and M3 (ChRM3) were examined.Tiotropium treatment significantly reduced airway inflammation and remodeling in asthmatic mice and intensified the lung function. PDCD5 level was reduced with tiotropium (p < 0.05). Moreover, active caspase-3 level was decreased with tiotropium (p < 0.001), and ChRM3 level was increased.Tiotropium treatment may alleviate the pathological changes with asthma by regulating apoptosis.
Tiotropium bromide
Cite
Citations (8)
ABSTRACT Background Chronic Obstructive Pulmonary Disease (COPD) affects an estimated 330 million individuals worldwide. Approximately, 3 million individuals died of COPD in 2012 and it is predicted that COPD would be the third leading factor for deaths worldwide by 2020. In United Kingdom nearly one million individuals suffer from COPD. Purpose There are no effective pharmacotherapies available for COPD. it is only managed by using bronchodilators and inhaled corticosteroids mostly. However, cardiovascular effects are associated with these drugs. Most importantly, there is an unmet need of COPD treatment worldwide. Our research aim was to identify Ipratropium and Tiotropium as novel anti-inflammatory agents in in vitro macrophage models. Aims To investigate the LPS stimulated pro-inflammatory cytokines IL-6 and TNF- α levels in THP-1 cells. To investigate whether the drugs Ipratropium and Tiotropium are capable of decreasing LPS-induced inflammation in THP-1 cells. Materials Human monocytic cell line THP-1 cells, Rosewell Park Memorial Institute RPMI 1640 with Glutamax I, 1% Penicillin Streptomycin (PenStrep) and 10% foetal bovine serum (FBS), Lipopolysaccharide 10μl/ml, 0.05% Tween20, 0.4% Trypan blue, Reagent diluent (10% Bovine Serum Albumin in PBS), Budesonide Fenoterol, Ipratropium and Tiotropium. Human IL-6 DuoSet ELISA, Human TNF-α ELISA, TMB ELISA Substrate solution and Stop solution. Methods THP-1 cells were cultured and challenges with LPS to stimulate the IL-6 and TNF-α cytokines. The cells were treated with Budesonide, Fenoterol, Ipratropium and Tiotropium. ELISA was performed to determine the concentrations of cytokines. Results The results suggested that Ipratropium and Tiotropium reduce IL-6 and TNF- α concentrations in the cells. However, Budesonide and Fenoterol were found to reduce cytokines more effectively than Ipratropium and Tiotropium. The data was considered significant only when P <0.05. Conclusions The anti-inflammatory or cytokine reducing properties of Ipratropium and Tiotropium were acknowledged. The research hypothesis was found to be true. Budesonide and Fenoterol substantially reduce cytokine levels. The receptor interactions of Ipratropium and Tiotropium may be responsible for their duration of action. Overall, Ipratropium and Tiotropium display the characteristics of novel anti-inflammatories.
Ipratropium
Fenoterol
Salmeterol
Tiotropium bromide
Cite
Citations (0)
Roflumilast is approved as an add-on therapy for chronic obstructive pulmonary disease. The inflammation in chronic obstructive pulmonary disease is mainly neutrophilic, while in asthma it is mainly eosinophilic, studies addressing role of roflumilast in eosinophilic inflammation are recommended. Also in severe asthma, the dominant inflammatory cells are neutrophils. Thus, roflumilast has a potential off-label use in the treatment of asthma. This study was designed to evaluate the effects of co-inhalation of roflumilast and fluticasone compared to that of formoterol and fluticasone in ovalbumin-sensitized and-challenged BALB/c mice. Besides normal control group, the ovalbumin-asthmatic mice were randomly divided into seven groups (n = 8): positive control, vehicle-treated, and five drug-treated groups. Treatments (µg/kg) were given as 15 min-inhalation once/day for five days as follows: roflumilast (500), formoterol (50), fluticasone (1000), roflumilast + fluticasone (500 + 1000), and formoterol + fluticasone (50 + 1000). Penh values were measured in conscious unrestrained mice using the single-chamber whole-body plethysmography. Airway hyperreactivity to inhaled methacholine was evaluated. Bronchoalveolar lavage fluid was used for the measurements of levels of IL-4, IL-5, TNF-α, OVA-specific IgE, and total and differential white cells. Lung sections were stained with hematoxylin and eosin and periodic acid-Schiff. The asthmatic mice showed significant increases in airway hyperreactivity which were significantly reversed by the combination treatments. The asthmatic mice showed significant increases in levels of IL-4, IL-5, TNF-α, ovalbumin-specific IgE, and total and differential white cells in bronchoalveolar lavage fluid. All treatments (except formoterol) significantly reversed these changes mainly with roflumilast + fluticasone. The asthmatic mice showed severe inflammatory infiltration and goblet cell hyperplasia which were maximally reversed by roflumilast + fluticasone, while minimally reversed by formoterol. In conclusion, co-inhalation of roflumilast + fluticasone more significantly improved inflammation and histopathological changes than co-inhalation of formoterol + fluticasone in ovalumin-asthmatic mice. Further studies are needed to help confirm the potential off-label add-on use of roflumilast in typical and atypical asthma and asthma-chronic obstructive pulmonary disease overlap syndrome. Impact statement Roflumilast, a selective phosphodiesterase-4 inhibitor, was approved for the treatment of chronic obstructive pulmonary disease (COPD). This study showed that co-inhalation of roflumilast and fluticasone significantly decreased airway hyperresponsiveness in ovalumin-asthmatic mice. Also, it more significantly improved inflammation and histopathological changes than co-inhalation of formoterol and fluticasone. The current results showed that inhaled roflumilast reduced counts of eosinophils, neutrophils, and macrophages in bronchoalveolar lavage fluid. Consequently, inhaled roflumilast might be of potential off-label benefit in treatment of eosinophilic and neutrophilic asthma and asthma-COPD overlap syndrome (ACOS). These results could also support other experimental and clinical studies addressing the same issue.
Fluticasone
Roflumilast
Methacholine
Formoterol Fumarate
Salmeterol
Cite
Citations (20)
Background: Smoking is a central risk factor for the development of Chronic Obstructive Pulmonary Disease (COPD) and Nontypeable Haemophilus Influenzae (NTHi) is expected to be an important trigger of exacerbations. Steroids, PDE-4 inhibitors and macrolides are used as treatment options. Aims and objectives: To investigate the effects of Dexamethasone, Roflumilast and Azithromycin in a murine cigarette smoke (CS)/NTHi infection model. Methods: Mice were exposed to CS and infected with NTHi. Animals were treated in a preventive manner with Dexamethasone, Roflumilast or Azithromycin each day of the experiment. Resistance and compliance were measured. Cell counts and bacterial load were determined in BAL fluid. Cytokines/chemokines were assessed in lung homogenate. Results: CS exposure and NTHi infection led to pulmonary neutrophil and macrophage accumulation. Pro-inflammatory cytokines/chemokines were elevated in lung homogenate. Dexamethasone, Roflumilast and Azithromycin treatment failed to reduce numbers of total cells and neutrophils. Moreover, dexamethasone treatment increased bacterial load and resulted in increased loss of body-weight. However, IFN-γ and IL-6 levels were reduced. Roflumilast had no pronounced effects on cytokines/chemokines but improved compliance. Treatment with azithromycin reduced bacterial load but had no effect on cytokines/chemokines or compliance. Conclusions: These results suggest that treatment with Dexamethasone, Roflumilast or Azithromycin might not be efficient to reduce CS and NTHi induced pulmonary inflammation. Treatment with Dexamethasone might increase the bacterial load, while Azithromycin could help to reduce the bacterial burden.
Roflumilast
Cite
Citations (0)
One of the major goals of asthma therapy is to maintain asthma control and prevent acute exacerbations. Long-acting bronchodilators are regularly used for the treatment of asthma patients and in clinical studies the anti-cholinergic tiotropium has recently been shown to reduce exacerbations in patients with asthma. So far it is unclear how tiotropium exerts this effect. For this purpose, we designed an allergen-driven rechallenge model of allergic airway inflammation in mice, to assess the effectiveness of tiotropium and the long-acting β-2 adrenoceptor agonist olodaterol on allergen-induced exacerbations of airway disease. Female C57BL/6J mice were sensitized intranasally (i.n.) with 1 μg of house dust mite (HDM) extract followed by a challenge regime (5 consecutive days 10 μg HDM extract i.n.) after one week. Mice were exposed to a secondary challenge five weeks after sensitization and were treated i.n. with different concentrations of tiotropium or olodaterol (1, 10 and 100 μg/kg) or a combination thereof (10 μg/kg each) prior to and during the secondary challenge period. Three days after the last challenge, bronchoalveolar lavage (BAL) fluid and lung tissue were collected for flow cytometry and histologic analysis, respectively. Secondary challenge with HDM extract strongly induced allergic airway disease reflected by inflammatory cell infiltration and goblet cell metaplasia. Treatment with tiotropium, but not with olodaterol reduced tissue inflammation and goblet cell metaplasia in a dose-dependent manner. The combination of tiotropium and olodaterol was more effective in significantly reducing tissue inflammation compared to tiotropium treatment alone, and also led to a decrease in BAL cell counts. These data suggest that in a model of relapsing allergic airway disease tiotropium directly prevents exacerbations by reducing inflammation and mucus production in the airways. In addition, the combination of tiotropium and olodaterol exerts synergistic effects.
Tiotropium bromide
Goblet cell
Combination therapy
Cite
Citations (10)