fluticasone and Airway-Remodeling

Steroid resistance in asthma has been associated with neutrophilic inflammation and severe manifestations of the disease. Macrolide add-on therapy can improve the quality of life and the exacerbation rate in refractory cases, possibly with greater effectiveness in neutrophilic phenotypes. The mechanisms leading to these beneficial effects are incompletely understood and whether macrolides potentiate the modulation of bronchial remodeling induced by inhaled corticosteroids (ICS) is unknown. The objective of this study was to determine if adding azithromycin to ICS leads to further improvement of lung function, airway inflammation and bronchial remodeling in severe asthma. The combination of azithromycin (10 mg/kg q48h PO) and inhaled fluticasone (2500 µg q12h) was compared to the sole administration of fluticasone for five months in a randomized blind trial where the lung function, airway inflammation and bronchial remodeling (histomorphometry of central and peripheral airways and endobronchial ultrasound) of horses with severe neutrophilic asthma were assessed. Although the proportional reduction of airway neutrophilia was significantly larger in the group receiving azithromycin, the lung function and the peripheral and central airway smooth muscle mass decreased similarly in both groups. Despite a better control of airway neutrophilia, azithromycin did not potentiate the other clinical effects of fluticasone.

Topics: Administration, Inhalation; Airway Remodeling; Animals; Anti-Bacterial Agents; Asthma; Azithromycin; Bronchodilator Agents; Drug Therapy, Combination; Female; Fluticasone; Horse Diseases; Horses; Male; Neutrophils

Smoking is as prevalent in asthmatics as in the general population. Asthmatic smokers benefit less from inhaled corticosteroids (ICS) than non-smoking asthmatics, possibly due to more smoking-induced small airways disease. Thus targeting small airways may be important in treating asthmatic (ex-)smokers. We hypothesized that extrafine particle ICS improve small airways function more than non-extrafine particle ICS in asthmatic (ex-)smokers.. We performed an open-label, randomized, three-way cross-over study comparing extrafine beclomethasone (HFA-QVAR) to non-extrafine beclomethasone (HFA-Clenil) and fluticasone (HFA-Flixotide) in 22 smokers and 21 ex-smokers with asthma (?5 packyears).. Similar effectiveness in improving small airways function was found for extrafine and non-extrafine particle ICS treatment for asthmatic smokers and ex-smokers.

Topics: Adenosine Monophosphate; Administration, Inhalation; Adrenal Cortex Hormones; Adult; Airway Remodeling; Asthma; Beclomethasone; Bronchial Provocation Tests; Cross-Over Studies; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Particle Size; Respiratory Function Tests; Smokers; Treatment Outcome

Periostin is a biomarker of eosinophilic airway inflammation and may contribute to airway remodeling in asthma. The anti-inflammatory activity of inhaled corticosteroids (ICS) for asthma control is widely recognized. The aim of this study was to assess the effects of ICS on serum periostin levels and its relationships to inflammation and airway geometry.. Forty-two healthy controls and 20 patients with steroid-naïve asthma before and after treatment with fluticasone propionate (800 μg/day for 16 weeks) were examined. Serum periostin, lung function and inflammatory cell counts in sputum were measured. Airway dimensions were determined by quantitative computed tomography (total area of the airway (Ao), wall area (WA), wall thickness (T) and percentage wall area (WA%) ).. Serum periostin concentrations were significantly higher in patients with asthma than in controls. Periostin levels were correlated with airway wall thickness and sputum eosinophilia and inversely correlated with airflow limitation in asthma. ICS significantly decreased serum periostin (P < 0.01), decreased WA corrected for body surface area (WA/BSA, P < 0.05), T/√BSA (P < 0.01) and WA% (P < 0.01), reduced the percentage of sputum eosinophils (P < 0.01) and improved airflow limitation. The decrease in serum periostin levels was associated with an increased per cent predicted forced expiratory volume in 1 s (r = -0.64, P < 0.01), decreased WA/BSA (r = 0.46, P < 0.05) and decreased sputum eosinophils (r = 0.71, P < 0.01).. Serum periostin levels respond partially to ICS and may reflect a reduction in airway inflammation and wall thickening in asthma.

Topics: Administration, Inhalation; Adult; Airway Remodeling; Asthma; Biomarkers; Cell Adhesion Molecules; Eosinophils; Female; Fluticasone; Glucocorticoids; Humans; Inflammation; Male; Middle Aged; Respiratory Function Tests; Sputum; Statistics as Topic; Tomography, X-Ray Computed; Treatment Outcome

We recently reported that epithelial-mesenchymal transition (EMT) is active in the airways in chronic obstructive pulmonary disease (COPD), suggesting presence of an active profibrotic and promalignant stroma. With no data available on potential treatment effects, we undertook a blinded analysis of inhaled corticosteroids (ICS) effects versus placebo on EMT markers in previously obtained endobronchial biopsies in COPD patients, as a "proof of concept" study.. Assessment of the effects of inhaled fluticasone propionate (FP; 500 μg twice daily for 6 months) versus placebo in 34 COPD patients (23 on fluticasone propionate and eleven on placebo). The end points were epidermal growth factor receptor (EGFR; marker of epithelial activation) and the biomarkers of EMT: reticular basement membrane (Rbm) fragmentation ("hallmark" structural marker), matrix metalloproteinase-9 (MMP-9) cell expression, and S100A4 expression in basal epithelial and Rbm cells (mesenchymal transition markers).. Epithelial activation, "clefts/fragmentation" in the Rbm, and changes in the other biomarkers all regressed on ICS, at or close to conventional levels of statistical significance. From these data, we have been able to nominate primary and secondary end points and develop power calculations that would be applicable to a definitive prospective study.. Although only a pilot "proof of concept" study, this trial provided strong suggestive support for an anti-EMT effect of ICS in COPD airways. A larger and fully powered prospective study is now indicated as this issue is likely to be extremely important. Such studies may clarify the links between ICS use and better clinical outcomes and protection against lung cancer in COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Airway Remodeling; Androstadienes; Australia; Biomarkers; Double-Blind Method; Drug Administration Schedule; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Fluticasone; Humans; Lung; Male; Matrix Metalloproteinase 9; Middle Aged; Pilot Projects; Prospective Studies; Pulmonary Disease, Chronic Obstructive; S100 Calcium-Binding Protein A4; S100 Proteins; Treatment Outcome

While most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling.. 22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks.. FP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP.. 200 μg/day of FP was as effective as 1000 μg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.

Topics: Administration, Inhalation; Adolescent; Adult; Airway Remodeling; Androstadienes; Anti-Asthmatic Agents; Asthma; Basement Membrane; Breath Tests; Cytokines; Female; Fluticasone; Humans; Inflammation; Lung; Macrophages, Alveolar; Male; Mannitol; Nitric Oxide; Respiratory Function Tests; Young Adult

Asthmatic airways are inflamed and undergo remodelling. Inhaled corticosteroids and long-acting β2-agonist combinations are more effective than inhaled corticosteroid monotherapy in controlling disease exacerbations, but their effect on airway remodelling and inflammation remains ill-defined. This study evaluates the contribution of inhaled fluticasone and salmeterol, alone or combined, to the reversal of bronchial remodelling and inflammation. Severely asthmatic horses (6 horses/group) were treated with fluticasone, salmeterol, fluticasone/salmeterol, or with antigen avoidance for 12 weeks. Lung function, central and peripheral airway remodelling, and bronchoalveolar inflammation were assessed. Fluticasone/salmeterol and fluticasone monotherapy decreased peripheral airway smooth muscle remodelling after 12 weeks (p = 0.007 and p = 0.02, respectively). On average, a 30% decrease was observed with both treatments. In central airways, fluticasone/salmeterol reversed extracellular matrix remodelling after 12 weeks, both within the lamina propria (decreased thickness, p = 0.005) and within the smooth muscle layer (p = 0.004). Only fluticasone/salmeterol decreased bronchoalveolar neutrophilia (p = 0.03) to the same extent as antigen avoidance already after 8 weeks. In conclusion, this study shows that fluticasone/salmeterol combination decreases extracellular matrix remodelling in central airways and intraluminal neutrophilia. Fluticasone/salmeterol and fluticasone monotherapy equally reverse peripheral airway smooth muscle remodelling.

Topics: Adolescent; Airway Remodeling; Animals; Antigens; Asthma; Bronchodilator Agents; Child; Disease Progression; Extracellular Matrix; Female; Fluticasone; Horses; Humans; Male; Muscle, Smooth; Neutrophil Infiltration; Neutrophils; Salmeterol Xinafoate; Severity of Illness Index; Young Adult

Chronic cough is associated with airway inflammation and remodelling. Abnormal airway smooth muscle cell (ASMC) function may underlie mechanisms of chronic cough. Our objective was to examine the transcriptome and focused secretome of ASMCs from chronic cough patients and healthy non-cough volunteers. ASMC gene expression profiling was performed at baseline and/or after stimulation with polyinosinic:polycytidylic acid (poly(I:C)) to mimic viral infection. Supernatants were collected for multiplex analysis. Our results showed no significant differentially expressed genes (DEGs, false discovery rate (FDR) <0.05) between chronic cough and healthy non-cough ASMCs at baseline. Poly(I:C) stimulation resulted in 212 DEGs (>1.5 fold-change, FDR <0.05) in ASMCs from chronic cough patients compared with 1674 DEGs in healthy non-cough volunteers. The top up-regulated genes included chemokine (C-X-C motif) ligand (CXCL) 11 (

Topics: Airway Remodeling; Anti-Inflammatory Agents; Antigens; Bronchi; Bronchoscopy; Chronic Disease; Cough; Cytokines; Cytoskeletal Proteins; Female; Fluticasone; Gene Expression Profiling; Humans; Immunity, Innate; Inflammation; Male; Middle Aged; Myocytes, Smooth Muscle; Pilot Projects; Poly C

Inhaled corticosteroids are the most effective treatment currently available for asthma, but their beneficial effect against airway remodeling is limited. The tyrosine kinase inhibitor nilotinib has inhibitory activity against c-kit and the platelet-derived growth factor receptor. We compared the effects of fluticasone and nilotinib on airway remodeling in a chronic asthma model. We also examined whether co-treatment with nilotinib and fluticasone had any synergistic effect in preventing airway remodeling.. We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized female BALB/c-mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated with fluticasone and/or nilotinib intranasally during the OVA challenge.. Mice chronically exposed to OVA developed eosinophilic airway inflammation and showed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Both fluticasone and nilotinib attenuated airway smooth muscle thickening. However, only nilotinib suppressed fibrotic changes, demonstrating inhibition of collagen deposition. Fluticasone reduced pro-inflammatory cells, such as eosinophils, and several cytokines, such as interleukin 4 (IL-4), IL-5, and IL-13, induced by repeated OVA challenges. On the other hand, nilotinib reduced transforming growth factor β1 levels in bronchoalveolar lavage fluid and inhibited fibroblast proliferation significantly.. These results suggest that fluticasone and nilotinib suppressed airway remodeling in this chronic asthma model through anti-inflammatory and anti-fibrotic pathways, respectively.

Topics: Administration, Intranasal; Airway Remodeling; Animals; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Cell Line; Cell Proliferation; Chronic Disease; Collagen; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Female; Fluticasone; Inflammation Mediators; Lung; Mice, Inbred BALB C; Muscle, Smooth; Ovalbumin; Protein Kinase Inhibitors; Pulmonary Fibrosis; Pyrimidines; Transforming Growth Factor beta1

The airway remodeling in asthma is associated with increased amount of matrix metalloproteinase (MMP)-9. High levels of MMP-9 were found in mucosal biopsies, sputum and in exhaled breath condensates (EBC) of asthma patients. However, there are no data concerning real in vivo activity. Inhaled corticosteroids are effective in asthma control, but it is unclear, whether they only attenuate inflammation, or also protect against progressive remodeling of respiratory tract. Therefore, the aim of the study was to assess the amount and activity of MMP-9 in context of pro-inflammatory cytokines (IL-6, IL-8 and tumor necrosis factor, TNF), measured in EBC of asthma-suffering children, treated with inhaled steroids. The study involved 27 children with asthma, continuously treated with inhaled fluticasone propionate, and 22 healthy controls. In addition to routine clinical screening, the selected cytokines in EBC were analyzed using Ultrasensitive ELISA, whereas activity of MMP-9 was assessed using a novel immunozymography method. Despite chronic treatment with inhaled steroids mean MMP-9/EBC activity in asthma group was significantly higher than in healthy controls. Moreover, high MMP-9/EBC in asthma-suffering children significantly correlated with IgE serum levels. The IL-6 and IL-8 concentration was below the detection limit in all EBC samples. TNF/EBC levels were similar in both, asthma and healthy children. We hypothesize that MMP-9 hyperactivity in asthma may be closely related to high IgE serum levels. Our results suggest that inhaled steroids may be ineffective to prevent asthma-associated airway remodeling. Finally, we emphasize the necessity of further research focused on MMP-9 inhibition in asthma treatment.

Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Airway Remodeling; Asthma; Breath Tests; Child; Cytokines; Exhalation; Female; Fluticasone; Humans; Immunoglobulin E; Inflammation Mediators; Male; Matrix Metalloproteinase 9; Time Factors

Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to increased airway narrowing in asthma. Increased ASM mass may be caused by exposure to mitogens, including platelet-derived growth factor (PDGF) and collagen type I, which induce a proliferative, hypocontractile ASM phenotype. In contrast, prolonged exposure to insulin induces a hypercontractile phenotype. Glucocorticosteroids and β₂-adrenoceptor agonists synergize to increase glucocorticosteroid receptor translocation in ASM cells; however, the impact of this synergism on phenotype modulation is unknown. Using bovine tracheal smooth muscle, we investigated the effects of the glucocorticosteroids fluticasone (10 nM), budesonide (30 nM), and dexamethasone (0.1-1 μM) and the combination of low concentrations of fluticasone (3-100 pM) and fenoterol (10 nM) on ASM phenotype switching in response to PDGF (10 ng/ml), collagen type I (50 μg/ml), and insulin (1 μM). All glucocorticosteroids inhibited PDGF- and collagen I-induced proliferation and hypocontractility, with the effects of collagen I being less susceptible to glucocorticosteroid action. At 100-fold lower concentrations, fluticasone (100 pM) synergized with fenoterol to prevent PDGF- and collagen I-induced phenotype switching. This inhibition of ASM phenotype switching was associated with a normalization of the PDGF-induced decrease in the cell cycle inhibitors p21(WAF1/CIP1) and p57(KIP2). At this concentration, fluticasone also prevented the insulin-induced hypercontractile phenotype. At even lower concentrations, fluticasone (3 pM) synergized with fenoterol to inhibit this phenotype switch. Collectively, these findings indicate that glucocorticosteroids and β₂-agonists synergistically inhibit ASM phenotype switching, which may contribute to the increased effectiveness of combined treatment with glucocorticosteroids and β₂-agonists in asthma.

Topics: Adrenergic beta-2 Receptor Agonists; Airway Remodeling; Androstadienes; Animals; Budesonide; Cattle; Cell Cycle; Cell Proliferation; Collagen Type I; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p57; Dexamethasone; Drug Synergism; Fenoterol; Fluticasone; Glucocorticoids; Insulin; Mitogens; Muscle Contraction; Muscle, Smooth; Myocytes, Smooth Muscle; Phenotype; Platelet-Derived Growth Factor; Respiratory System; Trachea

Recent studies suggest that airway smooth muscle remodeling is an early event in the course of asthma. Little is known of the effects of long-term antigen avoidance and inhaled corticosteroids on chronically established airway remodeling. We sought to measure the effects of inhaled corticosteroids and antigen avoidance on airway remodeling in the peripheral airways of horses with heaves, a naturally occurring asthma-like disease. Heaves-affected adult horses with ongoing airway inflammation and bronchoconstriction were treated with fluticasone propionate (with and without concurrent antigen avoidance) (n = 6) or with antigen avoidance alone (n = 5). Lung function and bronchoalveolar lavage were performed at multiple time points, and peripheral lung biopsies were collected before and after 6 and 12 months of treatment. Lung function improved more quickly with inhaled corticosteroids, but eventually normalized in both groups. Inflammation was better controlled with antigen avoidance. During the study period, corrected smooth muscle mass decreased from 12.1 ± 2.8 × 10(-3) and 11.3 ± 1.2 × 10(-3) to 8.3 ± 1.4 × 10(-3) and 7.9 ± 1.0 × 10(-3) in the antigen avoidance and fluticasone groups, respectively (P = 0.03). At 6 months, smooth muscle mass was significantly smaller compared with baseline only in the fluticasone-treated animals. The subepithelial collagen area was lower at 12 months than at baseline in both groups. During the study period, airway smooth muscle remodeling decreased by approximately 30% in both groups, although the decrease was faster in horses receiving inhaled corticosteroids. Inhaled corticosteroids may accelerate the reversal of smooth muscle remodeling, even if airway inflammation is better controlled with antigen avoidance.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Airway Remodeling; Airway Resistance; Androstadienes; Animals; Antigens, Plant; Asthma; Bronchioles; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Cell Proliferation; Collagen; Cytokines; Fluticasone; Horse Diseases; Horses; Inflammation Mediators; Lung; Monocytes; Muscle, Smooth; Organ Size; Proliferating Cell Nuclear Antigen; Respiratory Function Tests; Respiratory Mucosa; Treatment Outcome