pulmicort and Inflammation

This meta-analysis aimed to compare the efficacy of montelukast (MKST) combined with budesonide (BUD) and BUD alone in the treatment of pulmonary inflammation and pulmonary function in children with cough variant asthma (CVA). Five electronic databases were searched for studies about MKST+BUD therapy and BUD alone therapy on inflammation and pulmonary function in CVA children from inception to November 23, 2021. Twenty-two articles were included. The results showed that, compared with BUD alone, the combination treatment could achieve better improvement of pulmonary function and lower levels of inflammation (MKST+BUD group: FEV1: SMD = 2.77, 95% CI: 2.07, 3.46; FVC: SMD = 2.54, 95% CI: 1.82, 3.27; PEF: SMD = 2.27, 95% CI: 1.79, 2.75; IgE: SMD = -7.95, 95% CI: -9.66, -6.25; TNF-α: SMD = -4.67, 95% CI: -6.04, -3.31; IL-8: SMD = -8.18, 95% CI: -11.46, -4.90; BUD alone group: FEV1: SMD = 1.83, 95% CI: 1.34, 2.31; FVC: SMD = 1.39, 95% CI: 0.93, 1.84; PEF: SMD = 1.51, 95% CI: 1.13, 1.89; IgE: SMD = -4.93, 95% CI: -6.14, -3.72; TNF-α: SMD = -2.78, 95% CI: -3.76, -1.80; IL-8: SMD = -4.94, 95% CI: -7.10, -2.79). To conclude, compared with BUD alone, MKST+BUD therapy was found to be more effective in improving pulmonary function and reducing inflammation in CVA children. Key Words: Montelukast, Budesonide, Cough variant asthma, Children, Pulmonary function, Inflammatory markers, Meta-analysis.

Topics: Asthma; Budesonide; Child; Cough; Humans; Immunoglobulin E; Inflammation; Interleukin-8; Tumor Necrosis Factor-alpha

Eosinophilic oesophagitis is a unique form of non-IgE-mediated food allergy characterised by oesophageal eosinophilic infiltration. The prevalence of EoE has grown to currently represent the first cause of dysphagia and food impaction in children and young adults. Avoiding food triggers is the only therapy targeting the cause of the disease, but none of the currently available food allergy tests adequately predicts food triggers for EoE. Strategies based on the empirical elimination of food are the most effective and convenient in clinical practice. Proton pump inhibitors constitute an effective first-line therapy in half of patients, through a direct anti-inflammatory effect independent of its action on gastric acid secretion. Topical glucocorticosteroids budesonide and fluticasone reduce eosinophilic inflammation and reverse symptoms. This review includes the most relevant aspects of the epidemiology, diagnosis, treatment and monitoring of eosinophilic oesophagitis.

Topics: Adult; Anti-Inflammatory Agents; Budesonide; Child; Deglutition Disorders; Diet Therapy; Eosinophilic Esophagitis; Evidence-Based Practice; Fluticasone; Humans; Inflammation; Proton Pump Inhibitors; Young Adult

Crohn's disease (CD) is a chronic inflammatory disease of the digestive tract with systemic manifestations. Etiology is unknown, even if immunological, genetic and environmental factors are involved. The majority of CD patients require surgery during their lifetime due to progressive bowel damage, but, even when all macroscopic lesions have been removed by surgery, the disease recurs in most cases. Postoperative management represents therefore a crucial mean for preventing recurrence. Several drugs and approaches have been proposed to achieve this aim. Endoscopic inspection of the ileocolic anastomosis within 1 year from surgery is widely encouraged, given that endoscopic recurrence is one of the greatest predictors for clinical recurrence. A strategy should be planned only after stratifying patients according to their individual risk of recurrence, avoiding unnecessary therapies when possible benefits are reduced, and selecting high-risk patients for more aggressive intervention.

Topics: Anastomosis, Surgical; Anti-Bacterial Agents; Budesonide; Crohn Disease; Endoscopy; Gastroenterology; Humans; Inflammation; Mesalamine; Postoperative Period; Recurrence; Risk; Risk Factors; Treatment Outcome

Community-based clinical trials of the inhaled corticosteroid budesonide in early COVID-19 have shown improved patient outcomes. We aimed to understand the inflammatory mechanism of budesonide in the treatment of early COVID-19.. The STOIC trial was a randomised, open label, parallel group, phase 2 clinical intervention trial where patients were randomly assigned (1:1) to receive usual care (as needed antipyretics were only available treatment) or inhaled budesonide at a dose of 800 μg twice a day plus usual care. For this experimental analysis, we investigated the nasal mucosal inflammatory response in patients recruited to the STOIC trial and in a cohort of SARS-CoV-2-negative healthy controls, recruited from a long-term observational data collection study at the University of Oxford. In patients with SARS-CoV-2 who entered the STOIC study, nasal epithelial lining fluid was sampled at day of randomisation (day 0) and at day 14 following randomisation, blood samples were also collected at day 28 after randomisation. Nasal epithelial lining fluid and blood samples were collected from the SARS-CoV-2 negative control cohort. Inflammatory mediators in the nasal epithelial lining fluid and blood were assessed for a range of viral response proteins, and innate and adaptive response markers using Meso Scale Discovery enzyme linked immunoassay panels. These samples were used to investigate the evolution of inflammation in the early COVID-19 disease course and assess the effect of budesonide on inflammation.. 146 participants were recruited in the STOIC trial (n=73 in the usual care group; n=73 in the budesonide group). 140 nasal mucosal samples were available at day 0 (randomisation) and 122 samples at day 14. At day 28, whole blood was collected from 123 participants (62 in the budesonide group and 61 in the usual care group). 20 blood or nasal samples were collected from healthy controls. In early COVID-19 disease, there was an enhanced inflammatory airway response with the induction of an anti-viral and T-helper 1 and 2 (Th1/2) inflammatory response compared with healthy individuals. Individuals with COVID-19 who clinically deteriorated (ie, who met the primary outcome) showed an early blunted respiratory interferon response and pronounced and persistent Th2 inflammation, mediated by CC chemokine ligand (CCL)-24, compared with those with COVID-19 who did not clinically deteriorate. Over time, the natural course of COVID-19 showed persistently high respiratory interferon concentrations and elevated concentrations of the eosinophil chemokine, CCL-11, despite clinical symptom improvement. There was persistent systemic inflammation after 28 days following COVID-19, including elevated concentrations of interleukin (IL)-6, tumour necrosis factor-α, and CCL-11. Budesonide treatment modulated inflammation in the nose and blood and was shown to decrease IL-33 and increase CCL17. The STOIC trial was registered with ClinicalTrials.gov, NCT04416399.. An initial blunted interferon response and heightened T-helper 2 inflammatory response in the respiratory tract following SARS-CoV-2 infection could be a biomarker for predicting the development of severe COVID-19 disease. The clinical benefit of inhaled budesonide in early COVID-19 is likely to be as a consequence of its inflammatory modulatory effect, suggesting efficacy by reducing epithelial damage and an improved T-cell response.. Oxford National Institute of Health Research Biomedical Research Centre and AstraZeneca.

Topics: Adrenal Cortex Hormones; Antiviral Agents; Budesonide; COVID-19 Drug Treatment; Humans; Inflammation; Interferons; Respiratory Mucosa; SARS-CoV-2; Treatment Outcome

Whether cysteinyl-leukotriene receptor antagonists (LTRAs) have a similar antitussive effect to inhaled corticosteroids and long-acting β2-agonist (ICS/LABA), and that LTRA plus ICS/LABA is superior to LTRAs alone or ICS/LABA alone in treating cough variant asthma (CVA) remain unclear. This study aimed to investigate and compare the efficacy of montelukast alone, budesonide/formoterol alone and the combination of both in the treatment of CVA.. Ninety-nine CVA patients were assigned randomly in a 1:1:1 ratio to receive montelukast (M group: 10 mg, once daily), budesonide/formoterol (BF group: 160/4.5 μg, one puff, twice daily), or montelukast plus budesonide/formoterol (MBF group) for 8 weeks. The primary outcomes were changes in the cough visual analogue scale (VAS) score, daytime cough symptom score (CSS) and night-time CSS, and the secondary outcomes comprised changes in cough reflex sensitivity (CRS), the percentage of sputum eosinophils (sputum Eos%) and fractional exhaled nitric oxide (FeNO). CRS was presented with the lowest concentration of capsaicin that induced at least 5 coughs (C5). The repeated measure was used in data analysis.. Montelukast alone, budesonide/formoterol alone and a combination of both were effective in improving cough symptom, decreasing cough reflex sensitivity and alleviating eosinophilic airway inflammation in patients with CVA, and the antitussive effect and anti-eosinophilic airway inflammation were similar. Trial registration ClinicalTrials.gov, number NCT01404013.

Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Antitussive Agents; Asthma; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Capsaicin; Cough; Cyclopropanes; Formoterol Fumarate; Humans; Inflammation; Leukotriene Antagonists; Quinolines; Sulfides

The aim of this study was to explore the clinical effect of montelukast sodium chewable tablets combined with inhaled budesonide in the treatment of pediatric asthma and its influence on inflammatory factors. One hundred and thirty-five asthmatic children were randomly divided into montelukast sodium group, budesonide group and combined group. Clinical symptoms, lung function, inflammatory factors and immune related indices of patients in each group were observed and recorded. After treatment, the times to disappearance of wheezes, dyspnea, asthma and hospital stay in the combined group were significantly shorter than those in the single-drug group (all p < 0.001). Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), peak expiratory flow (PEF) were significantly higher than those before treatment, and in the combined group value were significantly higher than in the single-drug group in the same period (all p < 0.001). Tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-8 and hypersensitive C-reactive protein (hs-CRP) were significantly lower than before treatment, and the combined group was significantly lower than the single-drug group in the same period (all p < 0.05). The number of CD4

Topics: Acetates; Administration, Inhalation; Administration, Oral; Anti-Asthmatic Agents; Asthma; Budesonide; Child; Child, Preschool; Cyclopropanes; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Inflammation; Male; Quinolines; Respiratory Function Tests; Sulfides; Tablets; Treatment Outcome

We investigated the effects of ventilator mask atomization inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of acute exacerbation COPD (AECOPD) on circulating levels of inflammatory factors and prognosis.. A total of 86 cases of patients on ventilator support were randomly divided into control group and observation group with 43 cases each. The control group was administered routine treatment including basic disease treatment, anti-infection, maintenance of a stable internal environment, nutritional support, oxygen inhalation and so on. The control group was administered saline through a ventilator mask. The observation group was treated with atomized inhalation of ipratropium bromide and budesonide suspension and oxygen flow 3-5 L/min, 15-20 min/time and twice a day for 1 week. The treatment effects were compared.. Serum TNF-α, IL-6, and CRP levels were decreased in both groups after treatment, but levels in the observation group were significantly lower than those of the control group; differences were statistically significant (p < 0.05). Forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FVC and maximal expiratory flow rate in the observation group were significantly higher than those in the control group after treatment (p < 0.05). After treatment, the PaO2, SpO2 and respiratory failure index (RFI) of the observation group were significantly higher than those of the control group. The PaCO2 levels of the observation group were lower than those of the control group. The differences were statistically significant (p < 0.05). The clinical efficacy of the observation group was better than that of the control group; the ventilation time and total treatment time was significantly shorter and the differences were statistically significant (p < 0.05).. The ventilator mask atomizing inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of AECOPD can significantly improve circulating inflammatory reaction, improve lung function and blood gas levels, increase the treatment efficiency, and shorten the treatment time.

Topics: Administration, Inhalation; Aged; Blood Gas Analysis; Bronchodilator Agents; Budesonide; C-Reactive Protein; Female; Humans; Inflammation; Interleukin-6; Ipratropium; Male; Masks; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Respiration, Artificial; Respiratory Function Tests; Suspensions; Tumor Necrosis Factor-alpha

Corticosteroids have been shown to improve the outcome of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, whether inhaled corticosteroids (IC) alone have similar effects with systemic corticosteroid (SCS) is still unclear.. To compare the efficacy of inhaled budesonide and systemic methylprednisolone on systemic inflammation of AECOPD.. 30 AECOPD patients were randomly divided into two group. Budesonide group (15 cases) were treated with inhaled budesonide (3 mg Bid); methylprednisolone group (15 cases) were treated with systemic methylprednisolone (methylprednisolone acetate injectable suspension 40 mg Qd for three days and then methylprednisolone tablets 8 mg Bid). Observe symptoms, lung function, blood gas analysis and adverse effects of the patients in two groups. Peripheral blood samples were collected before and after treatment for 1 day, 4 days and 7 days. Interleukin-8 (IL-8) and TNF-α levels were determined by an enzyme linked immunosorbent assay (ELISA). Hs-CRP levels were detected by automatic biochemical analyzer. Western blotting was used to determine histone deacetylase 2 (HDAC2) protein expression.. Symptoms, pulmonary function and blood gas analysis were significantly improved after treatment in the two groups (P < 0.05) and no significant differences between the two groups (P > 0.05). There were no significant differences of IL-8, TNF-α and hs-CRP levels in the two groups (P > 0.05). Besides, the levels of HDAC2 protein expression before treatment were significantly lower comparing to that after treatment for 4 and 7 days. Incidence of adverse events (heart rate, blood pressure, glycemic, sleep condition, gastrointestinal symptoms) in budesonide group was lower than methylprednisolone group (P < 0.05).. Inhaled budesonide and systemic methylprednisolone have the same effects on systemic inflammation of AECOPD. Inhaled corticosteroid alone could instead systemic corticosteroid in AECOPD treatment.

Topics: Aged; Anti-Inflammatory Agents; Blood Gas Analysis; Budesonide; C-Reactive Protein; Drug Administration Routes; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Interleukin-8; Male; Methylprednisolone; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index; Tumor Necrosis Factor-alpha

The efficacy of montelukast (MONT), a cysteinyl leukotriene receptor antagonist, in nonasthmatic eosinophilic bronchitis (NAEB), especially its influence on cough associated life quality is still indefinite. We evaluated the efficacy of MONT combined with budesonide (BUD) as compared to BUD monotherapy in improving life quality, suppressing airway eosinophilia and cough remission in NAEB.. A prospective, open-labeled, multicenter, randomized controlled trial was conducted. Patients with NAEB (aged 18-75 years) were randomized to inhaled BUD (200 μg, bid) or BUD plus oral MONT (10 μg, qn) for 4 weeks. Leicester cough questionnaire (LCQ) life quality scores, cough visual analog scale (CVAS) scores, eosinophil differential ratio (Eos), and eosinophil cationic protein (ECP) in induced sputum were monitored and compared.. The control and MONT groups contained 33 and 32 patients, respectively, with similar baseline characteristics. Significant with-in group improvement in CVAS, LCQ scores, Eos, and ECP was observed in both groups during treatment. After 2-week treatment, add-on treatment of MONT was significantly more effective than BUD monotherapy for CVAS decrease and LCQ scores improvement (both P < 0.05). Similar results were seen at 4-week assessment (both P < 0.05). 4-week add-on therapy of MONT also resulted in a higher percentage of patients with normal sputum Eos (<2.5%) and greater decrease of ECP (both P < 0.05).. MONT combined with BUD was demonstrated cooperative effects in improvement of life quality, suppression of eosinophilic inflammation, and cough remission in patients with NAEB.

Topics: Acetates; Adolescent; Adult; Aged; Aged, 80 and over; Bronchitis; Budesonide; Cough; Cyclopropanes; Female; Humans; Inflammation; Male; Middle Aged; Quality of Life; Quinolines; Sulfides; Young Adult

Combination therapy with an inhaled corticosteroid (ICS) and a long-acting β2-agonist (LABA) in a single inhaler is the mainstay of asthma management. We previously showed that switching from salmeterol/fluticasone combination (SFC) 50/250 μg bid to a fixed-dose formoterol/budesonide combination (FBC) 9/320 μg bid improved asthma control and pulmonary functions, but not fractional exhaled nitric oxide (FeNO), in patients with asthma not adequately controlled under the former treatment regimen.. To assess whether switching from SFC to FBC improves peripheral airway/alveolar inflammation in asthma (UMIN000009619).. Subjects included 66 patients with mild to moderate asthma receiving SFC 50/250 μg bid for more than 8 weeks. Patients were randomized into FBC 9/320 μg bid or continued the same dose of SFC for 12 weeks. Asthma Control Questionnaire, 5-item version (ACQ5) score, peak expiratory flow, spirometry, FeNO, alveolar NO concentration (CANO), and maximal NO flux in the conductive airways (J'awNO) were measured.. Sixty-one patients completed the study. The proportion of patients with an improvement in ACQ5 was significantly higher in the FBC group than in the SFC group (51.6% vs 16.7%, respectively, p = 0.003). A significant decrease in CANO was observed in the FBC group (from 8.8 ± 9.2 ppb to 4.0 ± 2.6 ppb; p = 0.007) compared to the SFC group (from 7.4 ± 7.8 ppb to 6.4 ± 5.0 ppb; p = 0.266) although there was no significant difference in the changes in pulmonary functions between the 2 groups. Similar significant differences were found in the CANO corrected for the axial back diffusion of NO (FBC, from 6.5 ± 8.2 ppb to 2.3 ± 2.5 ppb; and SFC, from 4.3 ± 5.3 ppb to 3.9 ± 4.3 ppb). There was no difference in the changes in FeNO or J'awNO between the 2 groups.. Switching therapy from SFC to FBC improves asthma control and peripheral airway/alveolar inflammation even though there is no improvement in pulmonary functions, and FeNO in asthmatic patients.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Albuterol; Androstadienes; Asthma; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Inflammation; Male; Middle Aged; Nitric Oxide; Prospective Studies; Pulmonary Alveoli; Severity of Illness Index; Spirometry; Surveys and Questionnaires; Treatment Outcome

In an attempt to establish how treatment with inhaled extra-fine beclomethasone/formoterol (I-EF-BDP/F) formulation differs from other combinations of inhaled corticosteroid (ICS) and long acting beta-agonist (LABA), we studied lung function and markers of airway inflammation upon switching to the extra-fine formulation and after 8 weeks of treatment with it.. We carried out a real-life clinical observation of undercontrolled asthmatic patients switched over from dry powder inhalers of fluticasone/salmeterol and budesonide/formoterol to I-EF-BDP/F (Foster(®), Chiesi Farmaceutici S.p.A., Italy). The effects of 8-weeks of treatment were documented by means of visual analog scale (VAS), quality of life by Asthma Quality of Life Questionnaire (AQLQ), spirometry and markers of airway or systemic inflammation: exhaled breath temperature (EBT), blood eosinophils (Eos), and high sensitivity C-reactive protein (CRP). Before/after treatment differences between forced vital capacity percent of predicted (%FVC), a simple indicator of small airways involvement, were calculated and subjects were ranked accordingly to reflect the magnitude of the therapeutic response. Subjects above the 75th percentile (n = 15), "top responders", were then compared with those below the 25th percentile (n = 15) "poor responders".. On average, the 59 patients completing the study (mean age ± SD 51 ± 12 years, 38 women) had significant improvement in VAS and QLQ scores at the end of the treatment period (49.1 ± 2.4 vs. 73.1 ± 2.05 and 146.1 ± 2.7 vs. 176.7.1 ± 3.4 respectively, P < 0.001), but not in the inflammatory indicators (EBT, CRP and Eos). However, when comparing the "top responders" with the "poor responders", significant improvement in these inflammatory indicators was observed: EBT significantly decreased from 34.04/mean/± 0.30/s.e.m./[°C] to 33.57 ± 0.33, P = 0.003, Eos in blood fell from 381.7 ± 91.2 [cells/μL] to 244.2 ± 43.2, P = 0.02. Before/after treatment differences in hsCRP decreased significantly in the top responders compared with the poor responders (Mann-Whitney test, P = 0.04).. Asthmatic subjects who had the most improvement in FVC after transition to I-EF-BDP/F from other combined ICS/LABA preparations also demonstrated a significant decrease in some indicators of airway/systemic inflammation. These results support the notion that I-EF-BDP/F exerts an effect also at the level of the small airways through a reduction of the level of air trapping. Patients in whom inflammation of the small airways plays an important clinical role are the ones to derive most benefit from this small airways tailored treatment. However, improved compliance due to the "promise of a new drug" effect should also be considered as contributing to the treatment results.

Topics: Administration, Inhalation; Adult; Albuterol; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bronchodilator Agents; Budesonide; C-Reactive Protein; Drug Combinations; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Inflammation; Male; Middle Aged; Particle Size; Quality of Life; Spirometry; Statistics, Nonparametric; Treatment Outcome

A course of combination therapy with an inhaled corticosteroid (ICS) and a long-acting β(2) agonist (LABA) for asthma can improve lung function, asthma symptoms and reduce exacerbations. Because both medicinal substance and inhalation devices are associated with clinical efficacy, each ICS/LABA combination may have different features. This study aimed to compare the effects of two widely available formulations, budesonide/formoterol (BUD/FM) delivered by a Turbuhaler(®), and fluticasone/salmeterol (FP/SM) delivered by a Diskus(®), on small airway function and airway inflammation.. Asthmatic patients (n = 40) treated twice daily with FP/SM 250/50 μg with forced expiratory volume in 1 s values controlled above 80% of the predicted normal but with suspected persistent airway inflammation and small airway impairment were enrolled in the study. Patients were randomized into two groups, receiving either twice daily BUD/FM 320/9 μg or FP/SM 250/50 μg, and treatment efficacy was compared after 4 weeks. Outcomes included impulse oscillometry (IOS), fractional exhaled nitric oxide (FeNO), spirometry and Asthma Control Questionnaire (ACQ) scores.. Patients in the BUD/FM group showed significant improvements in their IOS and spirometry parameters of small airway function, FeNO values and ACQ scores, compared with the FP/SM group. There were good correlations between IOS parameters, FeNO and ACQ score changes over the course of the treatment.. BUD/FM twice daily significantly improved small airway impairment and airway inflammation in asthmatic patients, leading to a reduction in asthma symptoms and achievement of good asthma control. In addition, improvement of small airway function may improve airway inflammation and/or lead to better controlled asthma.

Topics: Adult; Albuterol; Androstadienes; Asthma; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Formoterol Fumarate; Humans; Inflammation; Male; Middle Aged; Nitric Oxide; Oscillometry; Spirometry

Combining inhaled corticosteroids with long-acting beta(2)-agonists results in improved asthma symptom control and fewer asthma exacerbations compared with those seen after inhaled corticosteroids alone. However, there are limited data as to whether these beneficial effects are due to enhanced anti-inflammatory actions or whether such combination therapies affect airway remodeling in patients with asthma.. We sought to determine the effects of inhaled budesonide/formoterol combination therapy versus inhaled budesonide alone or inhaled placebo on allergen-induced airway responses, airway inflammation, and airway remodeling.. Fourteen asthmatic subjects with dual responses after allergen inhalation were included in this prospective, randomized, double-blind, 3-period crossover study. Outcomes included early and late asthmatic responses, changes in airway responsiveness, sputum eosinophilia measured before and after allergen challenge, numbers of airway submucosal myofibroblasts, and smooth muscle area measured before and after study treatment.. Allergen-induced sputum eosinophilia was significantly reduced by combination treatment to a greater extent than by budesonide alone. Allergen inhalation resulted in a significant increase in submucosal tissue myofibroblast numbers and produced a significant decrease in percentage smooth muscle area. Combination therapy, but not budesonide monotherapy, significantly attenuated these changes in myofibroblast numbers and smooth muscle area.. The effects on allergen-induced changes in sputum eosinophils, airway myofibroblast numbers, and smooth muscle seen with combination therapy suggest that the benefits associated with this treatment might relate to effects on airway inflammation and remodeling. The attenuation of early asthmatic responses and airway hyperresponsiveness by combination treatment was likely due to the known functional antagonistic effect of formoterol.

Topics: Actins; Administration, Inhalation; Adult; Airway Remodeling; Asthma; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Combinations; Eosinophilia; Ethanolamines; Female; Formoterol Fumarate; Humans; Inflammation; Male; Microscopy, Electron, Transmission; Muscle, Smooth; Sputum

It is widely assumed that apoptosis of eosinophils is a central component of resolution of allergic airway disease. However, this has not been demonstrated in human allergic airways in vivo. Based on animal in vivo observations we hypothesised that steroid-induced resolution of human airway eosinophilic inflammation involves inhibition of CCL5 (RANTES), a CC-chemokine regulating eosinophil and lymphocyte traffic, and elimination of eosinophils without evident occurrence of apoptotic eosinophils in the diseased tissue.. To determine mucosal eosinophilia, apoptotic eosinophils, general cell apoptosis and cell proliferation, and expression of CCL5 and CCL11 (eotaxin) in human allergic airway tissues in vivo at resolution of established symptomatic eosinophilic inflammation.. Twenty-one patients with intermittent (birch and/or grass) allergic rhinitis received daily nasal allergen challenges for two seven days' periods separated by more than two weeks washout. Five days into these "artificial pollen seasons", nasal treatment with budesonide was instituted and continued for six days in a double blinded, randomized, placebo-controlled, and crossover design. This report is a parallel group comparison of nasal biopsy histochemistry data obtained on the final day of the second treatment period.. Treatments were instituted when clinical rhinitis symptoms had been established. Compared to placebo, budesonide reduced tissue eosinophilia, and subepithelial more than epithelial eosinophilia. Steroid treatment also attenuated tissue expression of CCL5, but CCL11 was not reduced. General tissue cell apoptosis and epithelial cell proliferation were reduced by budesonide. However, apoptotic eosinophils were not detected in any biopsies, irrespective of treatment.. Inhibition of CCL5-dependent recruitment of cells to diseased airway tissue, and reduced cell proliferation, reduced general cell apoptosis, but not increased eosinophil apoptosis, are involved in early phase steroid-induced resolution of human allergic rhinitis.

Topics: Administration, Intranasal; Adult; Anti-Allergic Agents; Antigens, Plant; Apoptosis; Betula; Biopsy; Budesonide; Cell Proliferation; Chemokine CCL11; Chemokine CCL5; Cross-Over Studies; Double-Blind Method; Eosinophilia; Female; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Male; Nasal Lavage Fluid; Nasal Mucosa; Placebo Effect; Poaceae; Pollen; Rhinitis, Allergic, Seasonal; Time Factors; Treatment Outcome; Young Adult

Cell resistance to glucocorticoids is a major problem in the treatment of nasal polyposis (NP).. The objectives of this study were to observe the effect of budesonide on the expression of IL-1beta, TNF-alpha, granulocyte macrophage-colony stimulating factor, intercellular adhesion molecule (ICAM)-1, basic fibroblast growth factor, eotaxin-2, glucocorticoid receptor (GR)-alpha, GR-beta, c-Fos and p65 in nasal polyps and to correlate their expression to clinical response.. Biopsies from nasal polyps were obtained from 20 patients before and after treatment with topical budesonide. Clinical response to treatment was monitored by a questionnaire and nasal endoscopy. The mRNA levels of the studied genes were measured by real-time quantitative (RQ)-PCR.. There was a significant decrease in the expression of TNF-alpha (P<0.05), eotaxin-2 (P<0.05) and p65 (P<0.05) in NP after treatment. Poor responders to glucocorticoids showed higher expression of IL-1beta (3.74 vs. 0.14; P<0.005), ICAM-1 (1.91 vs. 0.29; P<0.05) and p65 (0.70 vs. 0.16; P<0.05) before treatment. Following treatment, IL-1beta (4.18 vs. 0.42; P<0.005) and GR-beta (0.95 vs. 0.28; P<0.05) mRNA expression was higher in this group.. Topical budesonide reduced the expression of TNF-alpha, eotaxin-2 and p65. Poor responders to topical budesonide exhibit higher levels of IL-1beta, ICAM-1 and nuclear factor (NF)-kappaB at diagnosis and higher expression of both IL-1beta and GR-beta after treatment. These results emphasize the anti-inflammatory action of topical budesonide at the molecular level and its importance in the treatment of NP. Nevertheless, IL-1beta, ICAM-1 and NF-kappaB may be associated with primary resistance to glucocorticoids in NP, whereas higher expression of GR-beta in poor responders only after glucocorticoid treatment may represent a secondary drug resistance mechanism in this disease.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Budesonide; Cytokines; Drug Resistance; Endoscopy; Glucocorticoids; Humans; Inflammation; Inflammation Mediators; Middle Aged; Nasal Mucosa; Nasal Polyps; Predictive Value of Tests; Surveys and Questionnaires; Treatment Outcome; Young Adult

Budesonide/formoterol maintenance and reliever therapy maintains asthma control and reduces exacerbation frequency compared with higher fixed-dose combination regimens. Its effects on eosinophilic airway inflammation and structure are unknown.. We sought to compare the effects of budesonide/formoterol 200/6 microg twice daily plus as-needed with budesonide/formoterol 800/12 microg twice daily on airway eosinophils and remodeling.. This 52-week, parallel-group, randomized, double-blind study of 127 asthma patients who were symptomatic despite therapy compared (1) the change between induced sputum percent eosinophils at baseline and the geometric mean of 4 on-treatment values and (2) the change in endobronchial biopsy eosinophil counts pre- and post-treatment.. Mean daily doses of budesonide/formoterol were 604/18 microg in the maintenance and reliever therapy group and 1,600/24 microg in the high fixed-dose group. In the former, the geometric mean percent sputum eosinophils remained unchanged (1.6% to 1.9%), whereas biopsy specimen subepithelial eosinophils increased (6.2 to 12.3 cells/mm(2)). Sputum and biopsy eosinophil counts decreased with high fixed-dose treatment (2.2% to 1.2% and 7.7 to 4.8 cells/mm(2), respectively), resulting in significant treatment differences of 0.7% (ratio, 1.8; 95% CI, 1.2-2.8; P = .0038) and 7.5 cells/mm(2) (ratio, 2.9; 95% CI, 1.6-5.3; P < .001), respectively. There were no between-treatment differences in reticular basement membrane thickness, exhaled nitric oxide, exacerbation frequency, or FEV(1).. Compared with fixed-dose combination treatment containing a 4-fold higher maintenance dose of budesonide, budesonide/formoterol maintenance and reliever therapy is associated with higher eosinophil counts, but these remain within the range associated with stable clinical control.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Asthma; Blood Cell Count; Bronchodilator Agents; Budesonide; Double-Blind Method; Eosinophils; Ethanolamines; Female; Formoterol Fumarate; Humans; Inflammation; Male; Middle Aged; Young Adult

A beneficial effect of long-term corticosteroid treatment in patients with COPD may be linked to suppressing inflammation, in particular neutrophilic inflammation. Effects on neutrophilic and eosinophilic inflammation and on lung function of long-term inhaled budesonide treatment (800 microg daily, 6 months, double-blind, randomised, cross-over versus placebo) were studied and compared to the effects of 3 weeks oral prednisolone (30 mg daily) in 19 patients with COPD (mean age 63 y, FEV(1) 65% of predicted). Neither treatment influenced neutrophilic inflammation. Inhaled budesonide compared to placebo significantly reduced sputum % eosinophils at 3 months (-42%, p = 0.036), but not significantly at 6 months (-31%, p = 0.78). Eosinophil count per g sputum was decreased with 30% at 3 months (p = 0.09) and with 9% at 6 months (p = 0.78). FEV(1) was slightly higher after 6 months budesonide (+2.5% predicted, p = 0.09). Prednisolone significantly reduced sputum % eosinophils (-87%, p = 0.007), but did not affect eosinophil count per g sputum and did not improve FEV(1) (-0.6% predicted, p = 0.40). A higher baseline FEV(1) (%) correlated with effects of budesonide on FEV(1) (p < 0.001), effects on sputum interleukin-8 and eosinophil cationic protein (both p < 0.05) and tended to correlate with effects on sputum % eosinophils (p = 0.056). Baseline inflammatory data and effects of prednisolone did not correlate with effects of budesonide. Effects of inhaled budesonide in COPD are not restricted to patients with severe disease and may be linked to a suppression of eosinophilic inflammation. Investigating effects of prednisolone has no predictive value for long-term treatment.

Topics: Administration, Inhalation; Administration, Oral; Aged; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Eosinophils; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Inflammation; Male; Middle Aged; Neutrophils; Prednisolone; Pulmonary Disease, Chronic Obstructive; Sputum

To determine whether inhaled steroid administration after cardiopulmonary bypass will attenuate pulmonary inflammation and improve lung compliance and oxygenation.. Randomized, prospective, double-blind, placebo-controlled clinical trial.. Children's Hospital of Michigan, intensive care unit.. Thirty-two children <2 yrs of age with congenital heart disease requiring cardiopulmonary bypass.. Participants were randomly assigned to one of two groups. Group 1 (n = 16) received an inhaled steroid, Budesonide (0.25 mg/2 mL), and group 2 (n = 16) received an inhaled placebo (2 mL of inhaled 0.9% saline). The nebulizations were given at the end of cardiopulmonary bypass, 6 hrs after cardiopulmonary bypass, and 12 hrs after cardiopulmonary bypass. Two hours after each nebulization, bronchoalveolar lavage for interleukin-6 and interleukin-8 was collected.. The concentrations of interleukin-6 and interleukin-8 in the bronchoalveolar lavage increased in both groups after cardiopulmonary bypass. Interleukin-6 peaked 2 hrs after cardiopulmonary bypass and was decreasing by 14 hrs after cardiopulmonary bypass. However, administration of corticosteroid did not affect the production of interleukin-6 when compared with the placebo group (378 +/- 728 vs. 287 +/- 583 pg/mL pre-cardiopulmonary bypass, 1662 +/- 1410 vs. 1584 +/- 1645 pg/mL at the end of cardiopulmonary bypass, 2601 +/- 3132 vs. 3677 +/- 4935 pg/mL 2 hrs after cardiopulmonary bypass, and 1792 +/- 3100 vs. 1283 +/- 1344 pg/mL 14 hrs after cardiopulmonary bypass; p > .05). Likewise, interleukin-8 in the lavage fluid was similar in both the placebo and steroid groups at all time points (570 +/- 764 vs. 990 +/- 1147 pg/mL pre-cardiopulmonary bypass, 1647 +/- 1232 vs. 1394 +/- 1079 pg/mL at the end of cardiopulmonary bypass, 1581 +/- 802 vs. 1523 +/- 852 pg/mL 2 hrs after cardiopulmonary bypass, and 1652 +/- 1069 pg/mL vs. 1808 +/- 281 pg/mL 14 hrs after cardiopulmonary bypass; p > .05). Lung compliance and oxygenation were similar in both groups.. Cardiopulmonary bypass is associated with a pulmonary inflammatory response. Inhaled corticosteroid did not affect the pulmonary inflammatory response as measured by interleukin-6 and interleukin-8 concentrations in the lung lavage after cardiopulmonary bypass. Pulmonary mechanics and oxygenation were not improved by the use of inhaled corticosteroid.

Topics: Administration, Inhalation; Bronchoalveolar Lavage Fluid; Budesonide; Cardiopulmonary Bypass; Child; Double-Blind Method; Female; Glucocorticoids; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Lung; Lung Compliance; Male; Prospective Studies; Respiratory Distress Syndrome

Bronchodilator therapy is the first step treatment in patients with COPD. The beneficial effects of corticosteroids either in health status or in airway inflammation in COPD have been previously studied. The aim of this study was to evaluate whether adding inhaled corticosteroids to combined bronchodilator therapy has additive clinical and anti-inflammatory effects in COPD patients.. Thirty patients with COPD were included in the study. All patients were receiving inhaled anticholinergic and long-acting beta-2 agonist. Inhaled corticosteroid (budesonide 800 microg daily) was added to their current medications for 12 weeks. Before and after this treatment period, spirometric values and arterial blood gas parameters were determined, blood was drawn for measurement of serum inflammatory markers and sputum was induced.. All patients were male, mean age was 67.7+/-8.7 years and duration of disease was 9.7+/-4.3 years. The induced sputum total cell counts, eosinophil and neutrophil counts decreased with corticosteroid treatment. The induced sputum IL-8 and TNF-alpha levels decreased significantly (IL-8; 835.9+/-217 versus 378.4+/-105 pg/ml, p=0.0001, TNF-alpha; 320.7+/-129 versus 201.3+/-52 pg/ml, p=0.003). Serum inflammatory markers and sputum LTB4 levels did not change with treatment.. These results suggested that the addition of inhaled corticosteroids to combined bronchodilator therapy might have anti-inflammatory effects in patients with COPD.

Topics: Administration, Inhalation; Aged; Biomarkers; Bronchodilator Agents; Budesonide; Combined Modality Therapy; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Treatment Outcome

There is a need for controlled trials among children with asthma to evaluate and compare different markers of inflammation.. Our goal was to investigate the effect of withdrawal of inhaled budesonide on repeated measurements of exhaled NO (ENO), peripheral blood eosinophils (PBE), sputum/NAL/serum-eosinophil cationic protein (ECP), bronchial hyperresponsiveness (BHR) and forced expiratory volume in 1 s (FEV(1)) in children with allergic asthma.. Eighteen asthmatic children were randomly allocated to continue or discontinue use of inhaled budesonide. They were followed up, at six visits for 4 months with regular blood, serum, sputum, and NAL samples. Sixteen age-matched healthy children served as controls.. ENO, PBE, and S-ECP increased significantly in the withdrawal group (p < 0.05) but not in the continuous treatment group. No trend could be observed during the study for markers in sputum or in NAL in either group.. The present data provide evidence for the clinical usefulness of measuring ENO, PBE, and S-ECP and when combined they could help to avoid over- and undertreatment with corticosteroids in the growing child.

Topics: Adolescent; Anti-Inflammatory Agents; Asthma; Biomarkers; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Child; Eosinophil Cationic Protein; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Male; Nasal Lavage Fluid; Nitric Oxide; Sputum

The value of sputum induction in pediatric asthma lies in its potential to directly and noninvasively assess airway inflammation in children, because bronchoscopy and biopsy carry some risk. The Childhood Asthma Management Program (CAMP) study was designed to evaluate the long-term effects of budesonide and nedocromil compared with placebo in children with mild to moderate asthma across 8 centers.. At the Denver CAMP site, we sought to evaluate the safety of sputum induction, to determine differences in airway inflammation between treatment groups by using induced sputum analysis, and to examine correlations between other biomarkers and sputum eosinophils.. Sputum induction was performed, and exhaled nitric oxide, circulating eosinophil counts, and serum eosinophil cationic protein were obtained at treatment discontinuation and after washout. Spirometry and a methacholine challenge were also performed according to the CAMP protocol.. Ninety of 117 children provided an adequate sputum sample for analysis. In 9 subjects (3 nedocromil and 6 placebo), sputum induction resulted in bronchospasm. These subjects had greater disease severity, as measured by a lower median prebronchodilator FEV 1 percentage predicted (85.0% vs 96.0%; P =.024) and FEV 1 /FVC ratio (70.0% vs 79.0%; P =.0008); greater bronchodilator reversibility (16.5% vs 6.8%; P =.004); higher serum IgE (1390.0 vs 495.0 ng/mL; P =.017) and circulating eosinophil count (757.0 vs 282.0/mm 3; P =.04); greater use of prednisone (1.9 vs 0.9 courses per 100 person-years; P =.05); and greater supplemental inhaled steroid doses (85.3 vs 0 mg; P =.016). At treatment discontinuation, budesonide-treated patients had a lower median (1st, 3rd quartile) sputum percentage eosinophil (SPEos) (0.2% [0%, 1.2%] vs 0.8% [0.2%, 4.6%]; P =.03) compared with those treated with placebo; no significant difference was noted between nedocromil- and placebo-treated patients. Higher SPEos at the time of treatment discontinuation was associated with asthma worsening that required rescue prednisone (n = 23) during the washout period compared with patients who remained stable (3.6% [0.4%, 6.4%] vs 0.6% [0.2%, 3.2%] SPEos; P =.023). Finally, greater SPEos was associated with atopy, higher bronchodilator reversibility, lower FEV 1 /FVC ratio, higher exhaled nitric oxide levels, circulating eosinophils, sputum and serum eosinophil cationic protein, more prednisone courses during the treatment period, and greater asthma severity.. Sputum induction is a relatively noninvasive and safe procedure that can provide information on eosinophilic inflammation and treatment response and is also associated with several measures of asthma control. However, this procedure still remains a research tool in asthma because of its requirements for technical expertise.

Topics: Adolescent; Anti-Asthmatic Agents; Asthma; Budesonide; Eosinophils; Female; Humans; Inflammation; Leukocyte Count; Male; Nedocromil; Nitric Oxide; Respiratory Function Tests; Sputum; Treatment Outcome

Asthma is a chronic inflammatory disease that persists even during adequate therapy and asymptomatic episodes. We questioned whether "silent" chronic allergen exposure can induce and maintain airway inflammation and whether this still occurs during regular treatment with inhaled steroids. Twenty-six patients with house dust mite allergy and mild asthma (dual responders) participated in a parallel, double-blind study. All patients inhaled a low-dose of allergen on 10 subsequent working days (Days 1-5, 8-12). They were treated with 400 micro g budesonide once daily (n = 13) or placebo (n = 13) from Days -3 to 19. At baseline (Day -6) and on Days 5, 12, and 19 we measured the provocative concentration of methacholine causing a 20% fall in FEV(1) (PC(20)), and percent eosinophils, interleukin (IL)-5/interferon-gamma messenger RNA ratio (in sputum cells by real-time reverse transcription-polymerase chain reaction [RT-PCR]), and eosinophilic cationic protein (ECP) in induced sputum. Symptoms, peak expiratory flow (PEF), FEV(1), and exhaled nitric oxide (NO) were recorded repeatedly during the study. In the placebo group, repeated low-dose allergen exposure resulted in a significant increase in sputum eosinophils (p = 0.043), ECP (p = 0.011), IL-5/IFN-gamma messenger RNA ratio (p = 0.04), and in exhaled NO (p = 0.001), without worsening of symptoms, PEF, or baseline FEV(1) (p > 0.07). In the budesonide group, the changes in PC(20), sputum ECP, and exhaled NO were significantly different as compared with the placebo group (p < 0.03). We conclude that repeated low-dose allergen exposure in asthma can lead to airway inflammation without worsening of symptoms, which can be prevented by inhaled steroid treatment. This suggests that antiinflammatory therapy is beneficial during allergen exposure, even during asymptomatic episodes.

Topics: Administration, Inhalation; Adolescent; Adult; Allergens; Anti-Inflammatory Agents; Asthma; Budesonide; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Inflammation; Male; Respiratory Function Tests; Respiratory Tract Diseases; Severity of Illness Index

The debate as to whether asthma is a single or heterogeneous disease remains unresolved although pathological studies, mostly using fibreoptic bronchoscopy on small numbers of subjects, have emphasised the similarities between different clinical phenotypes.. Lower airway inflammation was assessed non-invasively using induced sputum in 34 normal controls and 259 adults with symptomatic asthma receiving treatment at steps 1-3 of the British Thoracic Society (BTS) guidelines. A subgroup of 49 patients treated with as required beta(2) agonists only who met BTS criteria for a step up in treatment were studied before and 2 months after treatment with inhaled budesonide 400 micro g twice daily.. There was considerable heterogeneity in induced sputum cell counts, particularly in non-atopic patients. A subgroup of 60 patients had a distinctive sputum cell profile with a neutrophil count higher than our normal range (>65.3%) and a normal sputum eosinophil count (<1.9%). These patients were older, predominantly female, and were more likely to be non-atopic but otherwise had similar clinical and physiological features to the group as a whole. Among the 49 subjects studied before and after inhaled budesonide, 11 patients had an isolated sputum neutrophilia. Following treatment, these patients showed significantly less improvement in visual analogue symptom scores (-5.5 v -19.4 mm; mean difference 13.9; 95% CI 0.7 to 27.0), forced expiratory volume in 1 second (FEV(1)) (-0.08 v 0.13 l; mean difference 0.21; 95% CI 0.03 to 0.39), and concentration of methacholine provoking a fall in FEV(1) of 20% or more (PC(20)) (0.15 v 1.29 doubling doses; mean difference 1.11; 95% CI 0.13 to 2.15) than the remaining 38 patients.. These results suggest the presence of a distinct subgroup of patients with mild to moderate asthma who have predominantly neutrophilic airway inflammation and who respond less well to treatment with inhaled corticosteroids.

Topics: Administration, Inhalation; Administration, Topical; Adult; Anti-Inflammatory Agents; Asthma; Budesonide; Eosinophilia; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Inflammation; Leukocytosis; Male; Sputum; Treatment Outcome; Vital Capacity

Inhaled corticosteroids are effective antiinflammatory therapy for asthma; however, they do not completely abolish allergen-induced airway inflammation. Leukotriene modifiers attenuate both early and late allergen responses and have antiinflammatory properties. We reasoned that treatment with budesonide and montelukast in combination might provide greater antiinflammatory effects than either drug alone, and the purpose of this study was to compare the effects of treatment with budesonide and montelukast, alone or in combination, on outcome variables after allergen inhalation. Ten subjects with asthma with dual responses after allergen inhalation were included in this randomized, double-blind, crossover study. Outcomes included early and late asthmatic responses, and changes in airway responsiveness and sputum eosinophilia, measured before and after challenge. Treatment with montelukast attenuated the maximal early asthmatic response compared with placebo (p < 0.001) and budesonide (p = 0.002). Both budesonide and montelukast, alone and in combination, attenuated the maximal late asthmatic response compared with placebo (p < 0.01). Budesonide and montelukast, alone and in combination, afforded protection against allergen-induced airway hyperresponsiveness (p < 0.05), although the treatment effect of budesonide was greater than that of montelukast (p < 0.05). Treatment with budesonide and montelukast, alone and in combination, also attenuated allergen-induced sputum eosinophilia. Thus, montelukast and budesonide attenuated allergen-induced asthmatic responses, airway hyperresponsiveness, and sputum eosinophilia, although combination treatment did not provide greater antiinflammatory effects than either drug alone.

Topics: Acetates; Administration, Inhalation; Administration, Oral; Anti-Inflammatory Agents; Asthma; Budesonide; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Humans; Inflammation; Leukotriene Antagonists; Prospective Studies; Quinolines; Respiratory Hypersensitivity; Respiratory System; Sulfides

The perception of bronchoconstriction may be modulated by airway inflammation. However, the effect of inhaled corticosteroid (ICS) treatment on perception in subjects with asthma has received limited study. The aim of this study was to determine the effect of inhaled budesonide on the perception of breathlessness induced by histamine challenge. Thirty-five subjects with poorly controlled asthma were randomized to receive budesonide (1,600 or 3,200 microg/d) for 8 wk, followed by 8 wk at 1,600 microg/d and subsequent downtitration according to a clinical algorithm. Borg scores were recorded during histamine challenges performed at baseline and at 8, 16, 24, 48, and 72 wk. Perception was estimated as the slope of Borg/% fall FEV(1). The Borg/FEV(1) slope increased significantly after 8 wk of budesonide (0.09 [0.08-0.12] to 0.15 [0.11-0.19], p = 0.002), and remained increased compared with baseline values at all subsequent visits. There were no significant differences in Borg/ FEV(1) slope between subjects who were and were not taking ICS at study entry. The magnitude of change in the Borg/FEV(1) slope did not differ significantly between treatment groups and was not related to changes in baseline FEV(1), airway hyperresponsiveness, blood eosinophils, or serum eosinophil cationic protein (ECP). We conclude that treatment with budesonide enhances the perception of airway narrowing, but the effect is unrelated to budesonide dose, or to changes in circulating eosinophil markers.

Topics: Administration, Inhalation; Adolescent; Adult; Algorithms; Asthma; Attitude to Health; Blood Proteins; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Dyspnea; Eosinophil Granule Proteins; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Inflammation Mediators; Leukocyte Count; Male; Middle Aged; Regression Analysis; Ribonucleases; Severity of Illness Index; Treatment Outcome

Markers of airway inflammation are needed for prediction of asthma deterioration and evaluation of disease severity. Few studies have focused on the dynamics of airway inflammation as reflected by the activity of the eosinophils and their proteins after withdrawal of inhaled corticosteroids.. Our goal was to investigate the effect of withdrawal of inhaled budesonide on eosinophil count in blood and eosinophil proteins in serum and urine and to relate the levels of these markers to the risk of symptoms of asthma, increased bronchial hyperresponsiveness, and deterioration of lung function.. Thirty-three children were randomly selected to continue or discontinue use of inhaled budesonide in a double-blind, placebo-controlled study. They were followed up for 4 months with regular analysis of blood, serum, and urine samples; lung function; and methacholine challenges. Eosinophil activity markers were analyzed. Age-matched healthy children provided reference data for all parameters measured.. The eosinophil number in blood and eosinophil protein levels in serum (serum eosinophil cationic protein [ECP] and serum eosinophil peroxidase [EPO]) increased significantly in the withdrawal group, and the difference between the groups was significant (P =.02 for all). Twenty-nine percent of the children in the withdrawal group remained symptom free. This subgroup had eosinophil counts at baseline below 350/microL, a serum ECP level below 15 microg/L, and a serum EPO level below 25 microg/L, each of which was related to a low risk of exacerbation (relative risk = 0.37, 0.48, and 0.37 respectively; P <.05 for all). All eosinophil markers were lower in the healthy children than in the symptom-free children with asthma.. Our data indicate that eosinophil count and/or ECP and EPO levels can be used to estimate the short-term risk of deterioration and the need for corticosteroid treatment in cases of mild and moderate allergic asthma.

Topics: Adolescent; Anti-Asthmatic Agents; Antigens, CD; Asthma; Biomarkers; Blood Proteins; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Child; Disease Progression; Double-Blind Method; Eosinophil Granule Proteins; Eosinophil Peroxidase; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Leukocyte Count; Male; Membrane Glycoproteins; Methacholine Chloride; Peroxidase; Peroxidases; Ribonucleases; Skin Tests; Spirometry; Tetraspanin 29

Repeated low-dose allergen challenge increases airway hyperresponsiveness and sputum eosinophils in atopic asthmatics. Inhaled corticosteroids attenuate the airway responses to high-dose allergen challenge, but have not been evaluated against repeated low dose challenge.. This study evaluates the effects of once daily treatments of two doses of inhaled budesonide on airway responses to repeated low-dose allergen challenge.. Eight atopic asthmatics with a dual airway responses to inhaled allergen were recruited into a randomized, double-blind crossover, placebo-controlled study. In the mornings of four consecutive days (day 1-day 4), subjects inhaled budesonide 100 microg, 400 microg, or placebo, 30 min before inhaling a concentration of allergen causing a 5% early fall in FEV1. Airway hyperresponsiveness to methacholine and sputum eosinophils were measured at baseline, on the afternoon of day 2, day 4, and 24 h after the last challenge. There was a 1-week washout between each of the three treatment periods.. The repeated low-dose allergen challenge induced increases in the percentage sputum eosinophils from 2.0 +/- 0.7% at baseline to 16.6 +/- 7.1% on day 4 (P = 0.002), and this effect was reduced by once daily budesonide 100 microg to 5.6 +/- 1.8% (P = 0. 01) and by once daily budesonide 400 microg to 3.1 +/- 0.9% (P = 0. 004). Also, the allergen-induced methacholine airway hyperresponsiveness which occurred by day 4 (P = 0.03) of the repeated low dose challenge was inhibited by budesonide 400 microg (P = 0.017).. Both budesonide 100 microg and 400 microg inhaled once daily significantly reduces allergen-induced sputum eosinophilia after repeated low dose challenge; however, only the higher dose also attenuates the allergen-induced airway hyperresponsiveness.

Topics: Adult; Allergens; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Female; Humans; Inflammation; Male; Middle Aged; Respiratory System

We wished to evaluate the effects of once-daily combination therapy on surrogate inflammatory markers.. Fifteen patients with atopic persistent asthma were evaluated (mean age, 32.4 years; FEV(1), 75.2% predicted) in a randomized, double-blind, double-dummy, placebo-controlled crossover study with a 1-week placebo washout period, comparing the following once-daily nighttime treatments: (1) formoterol (FM), 12 microg, for 2 weeks and FM, 24 microg, for 2 weeks; or (2) budesonide (BUD), 400 microg, for 2 weeks and BUD, 800 microg, for 2 weeks; or (3) FM, 12 microg, plus BUD, 400 microg, for 2 weeks and FM, 24 microg, plus BUD, 800 microg, for 2 weeks. Adenosine monophosphate (AMP) bronchial challenge, exhaled nitric oxide (NO), and serum eosinophilic cationic protein (ECP) were evaluated at 12 h postdosing after administration of each placebo and after 2 and 4 weeks of each treatment.. The results of AMP challenge (provocative concentration causing a 20% fall in FEV(1)) at 4 weeks showed significant (p<0.05) improvements after patients had received all active treatments compared to placebo (20 mg/mL), with FM plus BUD, 261 mg/mL, being superior (p<0.05) to FM alone, 82 mg/mL, but not to BUD, 201 mg/mL. NO and ECP showed significant (p<0.05) reductions compared to placebo with FM plus BUD or BUD alone but not with FM alone. Combination therapy was associated with optimal patient preference (rank order, FM plus BUD > FM > BUD; p<0.0005), highest domiciliary peak expiratory flow, and lowest rescue inhaler usage. All three treatments produced equivalent improvements in spirometry.. Patients preferred once-daily combination therapy, but this had no greater effect on inflammatory markers than therapy with BUD alone. FM alone had no anti-inflammatory activity but exhibited bronchoprotection. This emphasizes the importance of first optimizing anti-inflammatory control with inhaled corticosteroids before considering adding a regular long-acting beta(2)-agonist.

Topics: Adenosine Monophosphate; Administration, Inhalation; Adult; Asthma; Biomarkers; Blood Proteins; Breath Tests; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Eosinophil Granule Proteins; Eosinophils; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Inflammation; Male; Middle Aged; Nitric Oxide; Prognosis; Ribonucleases; Spirometry

We have previously shown that allergen inhalation by asthmatics is associated with increases in bone marrow eosinophil/basophil colony-forming cells (Eo/B-CFU), and increases in CD34(+) hemopoietic progenitors expressing the alpha-subunit of the IL-5 receptor (IL-5Ralpha). This study investigated the effect of inhaled corticosteroid on baseline numbers and allergen-induced increases in these parameters. Nine subjects with mild, stable asthma inhaled budesonide (400 microgram/d) for 8 d in a placebo-controlled, double-blind, randomized crossover study. On Day 7, subjects inhaled allergen, with bone marrow sampling before and 24 h after challenge. Budesonide inhalation significantly attenuated the allergen-induced early and late asthmatic responses, degree of increase in sputum and blood eosinophils, as well as the baseline numbers of total bone marrow CD34(+) cells (p < 0.05), CD34(+)IL-3Ralpha+ cells (p < 0.01) and IL-5-responsive Eo/B-CFU (p < 0.05). Allergen inhalation significantly increased Eo/B-CFU grown in the presence of IL-3, GM-CSF, or IL-5 alone (p < 0.05) and in combination (p < 0.01), as well as the number of CD34(+)IL-5Ralpha+ cells (p < 0.01). However, these increases in Eo/B-CFU and CD34(+)IL-5Ralpha+ cells were not affected by budesonide treatment. These data demonstrate that short-term inhaled budesonide treatment has a systemic effect in inhibiting the turnover of a subpopulation of bone-marrow-derived progenitors, but that inhalation of allergen overcomes this inhibitory effect.

Topics: Administration, Inhalation; Administration, Topical; Adult; Allergens; Anti-Inflammatory Agents; Asthma; Basophils; Blood Cells; Bone Marrow; Budesonide; Eosinophils; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Inflammation; Male; Respiratory System; Sputum; Stem Cells

Budesonide is a highly potent topical glucocorticosteroid that is characterized by low systemic availability as a result of high first-pass hepatic metabolism. The aim of this study was to evaluate the efficacy and safety of three doses of an enema preparation of budesonide in patients with active distal ulcerative colitis/proctitis.. In a double-blind multicenter trial, 233 patients were randomized to receive either a placebo enema or budesonide enema at a dose of 0.5 mg/100 mL, 2.0 mg/100 mL, or 8.0 mg/100 mL. The primary efficacy variables were an improvement of sigmoidoscopic inflammation grade, total histopathology score, and remission rates. Effects on cortisol concentrations were also assessed.. After 6 weeks of treatment, there was significant improvement in sigmoidoscopy and histopathology scores in the budesonide 2.0-mg and 8.0-mg dose groups compared with placebo. Remission was achieved in 19% of patients in the 2.0-mg budesonide group (P

Topics: Adult; Anti-Inflammatory Agents; Budesonide; Colitis, Ulcerative; Dose-Response Relationship, Drug; Double-Blind Method; Enema; Female; Humans; Inflammation; Male; Proctitis; Sigmoidoscopy; Treatment Outcome

The role of glucocorticoids in the treatment of chronic obstructive pulmonary disease (COPD) is controversial. We have previously described high numbers of neutrophils and high concentrations of the inflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), and of the cell activation markers eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), myeloperoxidase (MPO), and human neutrophil lipocalin (HNL) in COPD patients as compared with controls, and have postulated that the cytokines TNF-alpha and IL-8 play a role in propagating the inflammatory response in COPD. We have now studied the effects of inhaled and oral glucocorticoids on these inflammatory indices in induced sputum. Initially, we studied the effect of a 2-wk course of inhaled budesonide (800 mg twice daily for 2 wk) in 13 patients with severe COPD (mean FDV1: 35% predicted). There was no clinical benefit in either lung function or symptom scores, and no significant change in the inflammatory indices as measured by total and differential cell counts and concentrations of TNF-alpha eosinophil activation markers ECP and EPO, and neutrophil activation markers MPO and HNL. Because the lack of anti-inflammatory effect might have been due to poor drug delivery as a result of severe airflow limitation, we undertook a study examining the antiinflammatory effect of oral prednisolone (30 mg daily for 2 wk) in patients with COPD and undertook the same measurements in 10 patients with atopic asthma. Sputum eosinophil numbers, ECP, and EPO were significantly reduced in the asthmatic patients but were not modified in COPD. This confirms the clinical impression that inhaled steroids have little antiinflammatory effect, at least in the short term in this group of patients, and suggests that the inflammatory process in COPD is resistant to the antiinflammatory effect of glucocorticoids.

Topics: Administration, Inhalation; Administration, Oral; Administration, Topical; Aged; Anti-Inflammatory Agents; Asthma; Budesonide; Cytokines; Female; Glucocorticoids; Humans; Inflammation; Lung Diseases, Obstructive; Male; Middle Aged; Prednisolone; Pregnenediones; Respiratory Function Tests; Sputum

Bronchial hyperreactivity (BHR) is found in Sjögren's syndrome, as in a number of other conditions such as asthma. BHR associated with asthma can be effectively treated with corticosteroids or sodium cromoglycate. We treated 19 Sjögren's syndrome patients with BHR with inhaled budesonide and inhaled cromoglycate for 6 weeks each. None of the treatment had any significant effect on symptoms of hyperreactivity or lung function. There was no effect on BHR measured as methacholine reactivity. Primary Sjögren's syndrome is a disease with inflammation not only in the salivary and lacrimal glands but also in the pulmonary alveoli and the bronchi. The main inflammatory cell is the lymphocyte, whereas, in the bronchi in asthma, the eosinophil granulocyte is the characteristic inflammatory cell. The cause of the discrepancy with regard to treatability of BHR in asthma and in Sjögren's syndrome is not known. Possibly not all BHR is caused by inflammation. There is not a perfect correlation between inflammation and hyperreactivity even in asthma. Even in the bronchial inflammation and the asthma symptoms are easy to treat with anti-inflammatory medicines, a considerable component of BHR usually still remains, as measured with methacholine or histamine.

Topics: Adult; Aged; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Budesonide; Cromolyn Sodium; Cross-Over Studies; Drug Therapy, Combination; Female; Humans; Inflammation; Methacholine Chloride; Middle Aged; Pregnenediones; Prospective Studies; Sjogren's Syndrome

Corticosteroids are important in the treatment of inflammatory dermatoses, such as psoriasis. They have anti-inflammatory, anti-proliferative and immunosuppressive effects. In this study, the effect of budesonide on proliferation, inflammatory cells and cytokines in psoriasis was investigated. In order to elucidate the time course of the different effects of corticosteroid treatment in psoriasis, six patients were treated for 3 weeks with budesonide 0.025% ointment (Preferid), and biopsies were studied immunohistochemically, before treatment and after 1 and 3 weeks of treatment. Clinical scores together with staining with antibodies indicating proliferation, keratin 16, keratin 10, T-lymphocytes, monocytes, polymorphonuclear leukocytes, Langerhans cells, interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and intercellular adhesion molecule-1 (ICAM-1) were performed. 'Psoriasis area' and 'severity index' (PASI) scores were significantly reduced after 1 week and 3 weeks of treatment. Epidermal hyperproliferation (Ki-67 binding) and suprabasal keratin 16 (Ks8.12) expression decreased within 1 week, while keratin 10 (RKSE60) expression did not change. Five out of 6 patients showed cytokine levels (IL-1alpha, IL-6, IL-8, and TNF-alpha; detected immunohistochemically) in the normal range, while 1 patient had highly increased cytokine levels. In this patient, cytokine levels decreased during treatment. In 4 patients, showing high dermal ICAM-1 expression before treatment, a consistent reduction of ICAM-1 on endothelial cells was observed. The inflammatory infiltrate (T-lymphocytes (T11), monocytes/macrophages (WT14), polymorphonuclear leukocytes (PMN, anti-elastase)) was reduced to some extent after 3 weeks. The number of Langerhans cells (OKT6) did not change. These results indicate that the psoriatic lesions, although clinically comparable, show interindividual differences in cytokine expression. Corticosteroid treatment for 1-3 weeks improves clinical scores and hyperproliferation. Cytokine levels are reduced during steroid treatment in the patient who showed high levels before treatment. To suppress the infiltrate entirely, longer steroid treatment is probably necessary. This may explain the relapse seen after short term corticosteroid therapy.

Topics: Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Biomarkers; Budesonide; Cell Division; Cytokines; Female; Glucocorticoids; Humans; Immunohistochemistry; Inflammation; Inflammation Mediators; Keratins; Male; Middle Aged; Pregnenediones; Psoriasis; Time Factors

Chronic obstructive pulmonary disease (COPD) is a common disease in industrialised countries and responsible for a considerable morbidity and mortality. Cigarette smoking is the most important aetiological factor. The EUROSCOP trial aims at investigating the hypothesis that airway inflammation plays an important pathogenic role in the development of chronic obstructive airway disease in smokers. In cigarette smokers with poorly reversible airflow obstruction, the effect over 3 yrs of an inhaled glucocorticosteroid, budesonide 400 micrograms b.i.d., on the decline of lung function, measured as postbronchodilator forced expiratory volume in one second (FEV1), will be compared with that of placebo. The trial has been designed to detect a difference in yearly decline of at least 30 ml.year-1. The study is a parallel group, randomised, double-blind, multicentre study. Patients will be recruited from 47 centres in 12 countries in Europe. It will start with a run-in consisting of two 3 month periods. During the first 3 months, the patients will be offered a smoking cessation programme. All patients who have not stopped smoking during this period will enter the second half of the run-in where compliance with the dosage regimen will be tested. After these two periods, patients will be randomised to receive either inhaled budesonide, 400 micrograms b.i.d., or placebo for a period of 3 yrs.

Topics: Administration, Inhalation; Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Budesonide; Clinical Trials as Topic; Double-Blind Method; Europe; Female; Glucocorticoids; Humans; Inflammation; Lung Diseases, Obstructive; Male; Middle Aged; Pregnenediones; Research Design; Smoking

Ulcerative colitis is a multifactorial disease of the gastrointestinal tract which is caused due to chronic inflammation in the colon; it usually starts from the lower end of the colon and may spread to other portions of the large intestine, if left unmanaged. Budesonide (BUD) is a synthetically available second-generation corticosteroidal drug with potent local anti-inflammatory activity. The pharmacokinetic properties, such as extensive first-pass metabolism and quite limited bioavailability, reduce its therapeutic efficacy. To overcome the limitations, nanosized micelles were developed in this study by conjugating stearic acid with caffeic acid to make an amphiphilic compound. The aim of the present study was to evaluate the pharmacological potential of BUD-loaded micelles in a mouse model of dextran sulfate sodium-induced colitis. Micelles were formulated by the solvent evaporation method, and their physicochemical characterizations show their spherical shape under microscopic techniques like atomic force microscopy, transmission electron microscopy, and scanning electron microscopy. The in vitro release experiment shows sustained release behavior in physiological media. These micelles show cytocompatible behavior against hTERT-BJ cells up to 500 μg/mL dose, evidenced by more than 85% viable cells. BUD-loaded micelles successfully normalized the disease activity index and physical observation of colon length. The treatment with BUD-loaded micelles alleviates the colitis severity as analyzed in histopathology and efficiently, overcoming the disease severity via downregulation of various related cytokines (MPO, NO, and TNF-α) and inflammatory enzymes such as COX-2 and iNOS. Results of the study suggest that BUD-loaded nano-sized micelles effectively attenuate the disease conditions in colitis.

Topics: Animals; Budesonide; Colitis; Colitis, Ulcerative; Colon; Disease Models, Animal; Inflammation; Mice; Micelles

Acute lung injury (ALI) may result in severe systemic inflammation and is life-threatening. Remote inflammatory preconditioning (RIPC) has been confirmed to have an endogenous protective effect against ALI. Budesonide (BS) is a potent corticosteroid typically administered through nebulization that reduces inflammation in the lungs. We speculate that the combined use of RIPC and nebulized BS has a stronger protective effect on ALI.. 48 Sprague-Dawley male rats were used for the experiments. Animals were divided evenly and randomly into three groups, control (NS injection), LPS (LPS injection), and RIPC (LPS injection with RIPC). Each group was then divided into two subgroups with inhalation of nebulized normal saline (NS) or BS. Prior to injection of LPS, RIPC was performed by tying and untying the right hind limb for three cycles of 5 min each. Following LPS injection, animals in each subgroup were placed in a same cage for nebulized inhalation. Animals were sacrificed 6 h after LPS injection. Histological evaluation of ALI and lung wet-to-dry weight ratio were measured. Serum lactate acid, inflammatory cytokines, oxidative stress indicators were detected. The expression of HO-1, NF-κB p65 and p-p65 was measured by western blotting.. RIPC combined with nebulized BS significantly attenuated the LPS-induced ALI in rats. Reduction of MDA, increasing of SOD activity were found significantly improved by the joint strategy. TNF- and IL-1β rise brought on by LPS was reduced, but IL-10 production dramatically enhanced when compared to the LPS group. The expression of HO-1 was significantly increased by RIPC combined with nebulized BS while the expression of NF-κB p65 and p-p65 was decreased when compared with the LPS group.. RIPC combined with nebulized budesonide is protective for ALI induced by LPS in rats.

Topics: Acute Lung Injury; Animals; Budesonide; Inflammation; Lipopolysaccharides; Lung; Male; NF-kappa B; Rats; Rats, Sprague-Dawley

Inflammatory bowel disease (IBD) is characterized by chronic inflammation along the gastrointestinal tract. For IBD effective treatment, developing an orally administered stable drug delivery system capable of targeting inflammation sites is a key challenge. Herein, we report pH responsive hyaluronic (HA) coated Eudragit S100 (ES) nanoparticles (NPs) for the targeted delivery of budesonide (BUD) (HA-BUD-ES-NPs). HA-BUD-ES-NPs showed good colloidal properties (274.8 ± 2.9 nm and - 24.6 ± 2.8 mV) with high entrapment efficiency (98.3 ± 3.41%) and pH-dependent release profile. The negative potential following incubation in simulated gastrointestinal fluids reflected the stability of HA coat. In vitro studies on Caco-2 cells showed HA-BUD-ES-NPs biocompatibility and enhanced cellular uptake and anti-inflammatory effects as shown by the significant reduction in IL-8 and TNF-α. The oral administration of HA-BUD-ES-NPs in an acetic acid induced colitis rat model significantly mitigated the symptoms of IBD, and improved BUD therapeutic efficacy compared to drug suspension. This was proved via the improvement in disease activity index and ulcer score in addition to refined histopathological findings. Also, the assessment of inflammatory markers, epithelial cadherin, and mi-R21 all reflected the higher efficiency of HA-BUD-ES-NPs compared to free drug and uncoated formulation. We thus suggest that HA-BUD-ES-NPs provide a promising drug delivery platform for the management and site specific treatment of IBD.

Topics: Acetic Acid; Animals; Budesonide; Caco-2 Cells; Cadherins; Colitis; Humans; Hyaluronic Acid; Inflammation; Inflammatory Bowel Diseases; MicroRNAs; Nanoparticles; Rats

A novel formulation for Ulcerative Colitis (UC) treatment by rectal administration with budesonide liposomes (Bud. Bud. In UC mice model, Bud. Novel Bud liposomes complex in thermosensitive Gel effectively mitigated symptoms, alleviated macroscopic and microscopic colon damage, and reduced inflammatory reaction in UC mice, which might be a potential strategy for UC treatment.

Topics: Animals; Budesonide; Colitis, Ulcerative; Inflammation; Interleukin-10; Interleukin-6; Liposomes; Male; Mice; Tumor Necrosis Factor-alpha

Chronic rhinosinusitis (CRS) is a chronic inflammatory condition affecting the nasal and paranasal sinuses of approximately 11.5% of the United States adult population. Oral corticosteroids are effective in controlling sinonasal inflammation in CRS, but the associated adverse effects limit their clinical use. Topical budesonide has demonstrated clinical efficacy in patients with CRS. Herein, we investigated the systemic delivery of liposomes tethered with poly(ethylene glycol) (PEG) and loaded with budesonide in a murine model of CRS. PEGylated liposomes encapsulated with budesonide phosphate (L-BudP) were administered via tail vein injection, and the feasibility of L-BudP to reduce sinonasal inflammation was compared to that of free budesonide phosphate (F-BudP) and topical budesonide phosphate (T-BudP) treatment over a 14-day study period. Compared to a single injection of F-BudP and repeat T-BudP administration, a single injection of L-BudP demonstrated increased and prolonged efficacy, resulting in the significant improvement of sinonasal tissue histopathological scores (p < 0.05) with decreased immune cell infiltration (p < 0.05). Toxicities associated with L-BudP and T-BudP treatment, assessed via body and organ weight, as well as peripheral blood liver enzyme and differential white blood cell analyses, were transient and comparable. These data suggest that systemic liposomal budesonide treatment results in improved efficacy over topical treatment.

Topics: Adult; Animals; Budesonide; Chronic Disease; Humans; Inflammation; Liposomes; Mice; Polyethylene Glycols; Rhinitis; Sinusitis

In this article, we have explored the effects of endoscopic sinus surgery together with budesonide treatment on nasal function and serum inflammatory factors on patients with chronic sinusitis. We retrospectively analyzed 120 patients with chronic sinusitis who were admitted to our hospital from March 2018 to March 2021 and were eligible for this study. They were separated into 2 groups according to different treatments, that is, the control group (treated with endoscopic surgery alone) of 58 cases and observation group (treated with endoscopic sinus surgery combined with budesonide) with 62 cases. Treatment efficacy, surgical status, overall symptom score before and after treatment, nasal mucociliary clearance function, serum eosinophils (EOS), serum immunoglobulin E (IgE), serum inflammatory factors, and occurrence of adverse reactions of both groups were recorded and compared. Total effective rate in the observation group presented strikingly more positive compared with that among patients in control group (P<0.05), as well as the data recorded in terms of operation time, blood loss during surgery and postoperative improvement time of patients (P<0.05). Overall symptom score, nasal mucociliary clearance, EOS, IgE and serum inflammatory factors in both groups were improved notably after treatment, while the observation group held a more obvious improvement. And it also had a markedly lower incidence of adverse reaction (P<0.05). Endoscopic sinus surgery combined with budesonide in the treatment of chronic sinusitis could effectively improve the clinical symptoms of patients, reestablish the function of the nasal cavity and improve their inflammation level. Meanwhile, it was of high safety and is worthy of clinical promotion.

Topics: Budesonide; Chronic Disease; Endoscopy; Humans; Immunoglobulin E; Inflammation; Nasal Cavity; Retrospective Studies; Sinusitis

CD8+CD25+Foxp3+ regulatory T cells (Tregs) play an important role in human's immune tolerance. The study was aimed to assess the influence of budesonide nasal spray on CD8+CD25+Foxp3+ Tregs and to evaluate their cellular functions in neutrophilic chronic rhinosinusitis with nasal polyps (CRSwNPs).. Fifteen patients with neutrophilic CRSwNPs were enrolled and received physiological saline or budesonide nasal spray treatment (Saline or Budesonide group) for 3 months. Nasal tissue samples were obtained from normal subjects or those patients and cultured in vitro. CD8+CD25+Foxp3+ Tregs were separated from normal or NP tissues and also cultured in vitro. Then interleukin (IL)-10 and its mRNA were evaluated in the above cell cultures. The cells were applied into NP cultures. Finally, myeloperoxidase (MPO), interferon (IFN)-γ, IL-1β, and tumor necrosis factor (TNF)-α were assessed in the tissue cultures.. CD8+CD25+Foxp3+ Tregs decreased in NP tissues. Budesonide administration did not enhance the percentage of these cells in polypoid tissues. IL-10 and its mRNA were increased in the above cell cultures from NPs. However, there were no statistical differences between the two treatments in the IL-10 expression. Additionally, levels of MPO, IFN-γ, IL-1β, and TNF-α were totally elevated in NP tissue cultures and reduced after the administration of CD8+CD25+Foxp3+ Tregs. However, there were no significant differences in concentrations of these mediators between these two groups of the CD8+CD25+Foxp3+ Tregs treatment in vitro.. The findings indicate that CD8+CD25+Foxp3+ Tregs might regulate the neutrophilic inflammation, and budesonide nasal spray therapy could not ameliorate the inflammation in neutrophilic CRSwNPs.

Topics: Adrenal Cortex Hormones; Budesonide; CD8-Positive T-Lymphocytes; Forkhead Transcription Factors; Humans; Inflammation; Interferons; Interleukin-10; Nasal Polyps; Nasal Sprays; Peroxidase; Rhinitis; RNA, Messenger; Sinusitis; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

Alternative medicine, has become popular in asthmatic patients. We evaluated the immunomodulatory effects of SINA 1.2 therapy protocol derived from Persian medicine in an asthmatic mice model. Forty-two male BALB/c mice divided into six groups: one control (sham) and five sensitized groups (by parenteral injection of 20 μg ovalbumin in 100 μL normal saline plus 50 μL alum on days 1 and 14). Sensitized groups were as: untreated, budesonide (1 mg nebulized budesonide: 200 μg/puff every 5 min for 25 min), dry sauna (30 min, 37°C), oral oxymel (gavaged: 0.2 mL of the syrup plus 0.8 mL of water), and SINA protocol No.1.2 (oxymel followed by sauna) groups. Treatments were given for 10 days from day 23 to 33 then sacrificed. Significant gene expression reduction of interleukin(IL)-4, IL-5, and MUC5AC and increase of interferon(IFN)-γ and IFN-γ/IL-4 ratio and decreased perivascular and peribronchial inflammation, goblet cell hyperplasia, and subsequent mucus hypersecretion in SINA group were seen compared to untreated group. SINA lowered IL-5 and MUC5AC gene expression levels similar to the budesonide and acted better than budesonide in increasing IFN-γ gene expression up to normal level. Compared with the asthma group, sauna alone only affected MUC5AC and IFN-γ gene expressions and oxymel alone, only reduced IL-4 gene expression, perivascular and peribronchial inflammation, and mucus hypersecretion. It seems that SINA therapy alleviates asthma via immune modulation of pro-inflammatory cytokines and improvement of pathological changes in ovalbumin-induced asthma in mice, supporting the notion of innate healing power mentioned in Persian medicine literature.

Topics: Animals; Asthma; Budesonide; Humans; Inflammation; Interleukin-4; Interleukin-5; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Steam Bath

Ouabain, an inhibitor of Na+/K+-ATPase, is a type of endogenous hormone synthesized in the adrenal cortex and hypothalamus. Previous studies found that ouabain potently inhibited acute inflammatory reactions such as type 2 inflammation and regulated immunological processes. In this study, we aimed to investigate ouabain effect on allergic asthma.. BALB/c mice were submitted to chronic airway allergic inflammation induced by an ovalbumin (OVA) protocol. The animals were treated with ouabain or standard drug, budesonide. The following parameters were evaluated: cell migration, cytokine profile, IgE levels, lung histological modifications and MAPK activation.. At first, it was observed that ouabain reduced OVA-induced cell migration into the lung, observed by bronchoalveolar lavage fluid (BALF) cell counting and lung histological analysis (HE stain). Additionally, ouabain negatively modulated alarmins (IL-33 and TSLP), Th2 high cytokines levels (IL-1β and IL-4) and tissue remodeling markers such as TNF-α and TGF-β. Treatment with ouabain also reduced OVA-specific IgE titers in BALF and serum, respectively, when compared to the OVA group. Lung histological parameters, including collagen deposition and mucus production induced by OVA were also attenuated by ouabain treatment. Finally, our results showed that p38 mitogen-activated protein kinase (MAPK) signaling pathways were suppressed by ouabain in this model. All these parameters were reduced by budesonide, a steroidal anti-inflammatory standard drug.. These data together suggest that, in addition to its acute anti-inflammatory action, ouabain is also able to modulate allergic asthma.

Topics: Airway Remodeling; Animals; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Budesonide; Cytokines; Disease Models, Animal; Immunoglobulin E; Inflammation; Lung; Mice; Mice, Inbred BALB C; Ouabain; Ovalbumin

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that is still not well understood in terms of its pathogenesis and presents diagnostic and therapeutic challenges. Monocytes are key players in initiating and maintaining inflammation through the production of pro-inflammatory cytokines and S100 proteins in RA. This study aimed to test a specific DNA methylation inhibitor (RG108) and activator (budesonide) in the regulation of pro-inflammatory mediators-especially the S100 proteins. We also searched for new biomarkers of high disease activity in RA patients. RNA sequencing analysis of healthy controls (HCs) and RA monocytes was performed. Genes such as the S100 family, TNF, and IL-8 were validated by qRT-PCR following DNA-methylation-targeted drug treatment in a monocytic THP-1 cell line. The concentrations of the S100A8, S100A11, and S100A12 proteins in the sera and synovial fluids of RA patients were tested and correlated with clinical parameters. We demonstrated that RA monocytes had significantly increased levels of S100A8, S100A9, S100A11, S100A12, MYD88, JAK3, and IQGAP1 and decreased levels of IL10RA and TGIF1 transcripts. In addition, stimulation of THP-1 cells with budesonide statistically reduced the expression of the S100 family, IL-8, and TNF genes. In contrast, THP-1 cells treated with RG108 had increased levels of the S100 family and TNF genes. We also revealed a significant upregulation of S100A8, S100A11, and S100A12 in RA patients, especially in early RA compared to HC sera. In addition, protein levels of S100A8, S100A11, and S100A12 in RA synovial fluids compared to HC sera were significantly increased. Overall, our data suggest that the S100A8 and S100A12 proteins are strongly elevated during ongoing inflammation, so they could be used as a better biomarker of disease activity than CRP. Interestingly, epigenetic drugs can regulate these S100 proteins, suggesting their potential use in targeting RA inflammation.

Topics: Arthritis, Rheumatoid; Biomarkers; Budesonide; Calgranulin A; Calgranulin B; Epigenesis, Genetic; Homeodomain Proteins; Humans; Inflammation; Interleukin-8; Repressor Proteins; S100 Proteins; S100A12 Protein

Rheumatoid arthritis (RA) is a chronic autoimmune disorder and serious cause of disability. Despite considerable advances in RA management, challenges like extensive drug metabolism and rapid clearance causes poor bioavailability. Core-shell nanocarriers for co-delivery of glycyrrhizic acid (GA) and budesonide against RA were developed. GA-loaded gelatin nanoparticles (NPs) were synthesized and coated with budesonide encapsulated aminocellulose-grafted polycaprolactone (PCL-AC). GA- and budesonide-loaded PCL-AC-gel NPs had diameter of 200-225 nm. Dual drug-loaded (DDL) NPs reduced joint swelling and erythema in rats while markedly ameliorating bone erosion evidenced by radiological analysis, suppressed collagen destruction, restored synovial tissue, bone and cartilage histoarchitecture with reduced inflammatory cells infiltration. NPs also reduced various inflammatory biomarkers such as TNF-α, IL-1β, COX-2, iNOS. Results of this study suggest that dual NPs exerted superior therapeutic effects in RA compared to free drugs which may be attributed to slow and sustained drug release and NPs' ability to inhibit inflammatory mediators.

Topics: Animals; Arthritis, Rheumatoid; Biomarkers; Bone and Bones; Budesonide; Cartilage; Cellulose; Collagen; Cyclooxygenase 2; Drug Delivery Systems; Female; Fibroblasts; Gelatin; Glycyrrhizic Acid; Humans; Inflammation; Interleukin-1beta; Kinetics; Magnetic Resonance Spectroscopy; Nanoparticles; Nitric Oxide Synthase Type II; Polyesters; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Glucocorticoids (GCs) are widely used to treat a variety of autoimmune and inflammatory diseases; however, systemic delivery of GCs is associated with side effects that affect essentially every organ system, reflecting the nearly ubiquitous expression of the glucocorticoid receptor (GR). Targeted delivery of GCs to diseased tissues using antibody-glucocorticoid conjugates (GC-ADCs) offers a therapeutic alternative to overcome these adverse effects. Herein, we describe novel classes of GCs that exhibited greater potency than dexamethasone and budesonide, a 100-fold selectivity toward the GR over other nuclear receptors, and no

Topics: Animals; Budesonide; Cathepsin B; Glucocorticoids; Humans; Immunoconjugates; Inflammation; Lipopolysaccharides; Male; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Receptors, Glucocorticoid; Receptors, Prolactin; Structure-Activity Relationship

Asthma in elderly patients causes excessive suffering and inconvenience. Regimens with better efficacy and less adverse events are still in need of researches.. To investigate the effect of montelukast sodium plus budesonide on lung function, inflammatory factors, and immune levels in elderly asthma patients.. A total of 180 patients with asthma were assigned into the control group and the observation group. The control group was given aerosol inhalation of budesonide suspension, while the observation group was given budesonide inhalation and oral montelukast sodium. The treatment effect, lung function (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF)%), inflammatory factors (interleukin (IL)-4, IL-6, and tumor necrosis factor-α (TNF-α)), and immune level (immunoglobulin (Ig) A, and IgE) were analyzed and compared between the two groups.. After treatment, the effective rate was significantly higher in the observation group. The lung function and serum inflammatory factors were improved in both groups. The FEV1, FVC, and PEF% in the observation group were better, and the inflammatory factors IL-4, IL-6, and TNF-α were lower. Patients in both groups showed elevated IgA level and reduced IgE level, and the improvements were more significant in the observation group. There was no significant difference between the two groups in terms of adverse reaction.. Montelukast sodium plus budesonide has a promising clinical effect on asthma in elderly patients, effectively improves lung function and immunocompetence, and controls inflammatory response, without increasing the adverse reaction.

Topics: Acetates; Aged; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Budesonide; Cyclopropanes; Female; Humans; Inflammation; Male; Middle Aged; Quinolines; Respiratory Function Tests; Sulfides

Inflammatory bowel disease (IBD) affects a confined area of the intestine and, therefore, administration of drugs via oral route is preferable. However, obstacles such as changes in the pH along gastrointestinal tract (GIT), enzymatic activity, and intraluminal pressure may cause low drug availability in the target tissue when delivered orally. Previous studies have pointed out the benefits of using micron-sized particles for targeting inflamed intestinal mucosa and nanoparticles for delivery of anti-inflammatory agents to the affected epithelial cells. We hypothesized that by combining the benefits of micro- and nano- particles, we could create a more efficient delivery system for budesonide, a glucocorticosteroid commonly used for anti-inflammatory IBD therapy. The aim of this study was to develop a novel multistage system for oral delivery designed to increase concentrations budesonidein the inflamed intestinal tissue. The multistage system consists of Stage 1 mesoporous silicon microparticles (S1MP) loaded with stage 2 poly-lactic-glycolic acid (PLGA) budesonide-encapsulating nanoparticles (BNP). BNP were efficiently loaded into S1MP (loading efficiency of 45.9 ± 14.8%) due to the large pore volume and high surface area of S1MP and exhibited controlled release profiles with enhanced drug dissolution rate in biologically relevant pHs. Due to the robustness in acidic pH and their geometry, S1MP protected the loaded budesonide in the acidic (gastric) pH with only 20% release. This allowed for the prolonged release of the BNP in the higher pH conditions (intestinal pH). The sustained release of BNP could facilitate accumulation in the inflamed tissue, enabling BNP to penetrate inflamed mucosa and release active budesonide to the target site. The multistage systems of S1MP and BNP were further evaluated in three-dimensional (3D) in vitro model of IBD and were found to (1) increase accumulation of BNP in the inflamed areas, (2) restore the barrier function of Caco-2 inflamed monolayer, and (3) significantly reduce pro-inflammatory cytokine release almost to the level of the healthy control.

Topics: Anti-Inflammatory Agents; Budesonide; Caco-2 Cells; Cell Line, Tumor; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Hydrogen-Ion Concentration; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Nanoparticles; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Silicon; Solubility

Inhaled glucocorticoids form the mainstay of asthma treatment because of their anti-inflammatory effects in the lung. Exposure to the air pollutant ozone (O

Topics: A549 Cells; Administration, Inhalation; Allergens; Animals; Aspergillus fumigatus; Asthma; Bronchoalveolar Lavage Fluid; Budesonide; Cells, Cultured; Chemokine CCL11; Eosinophils; Glucocorticoids; Humans; Inflammation; Interleukin-13; Lung; Mice, Inbred BALB C; Oxidants, Photochemical; Ozone; Pulmonary Surfactant-Associated Protein D

A self-assembled and oxidation-degradable Janus-prodrug, termed as Bud-ATK-Tem (B-ATK-T), was fabricated by ROS-responsive aromatized thioketal (ATK) linked anti-inflammatory drug budesonide (Bud) and antioxidant tempol (Tem). Benefiting from the hydrophobic interactions and π-π stacking interactions of ATK, prodrug B-ATK-T could self-assemble into nanoparticles (NP) in water containing lecithin and DSPE-PEG

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Budesonide; Cyclic N-Oxides; Disease Models, Animal; Drug Delivery Systems; Drug Liberation; Inflammation; Inflammatory Bowel Diseases; Macrophages; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Prodrugs; RAW 264.7 Cells; Reactive Oxygen Species; Spin Labels

Chlorine is a chemical threat agent that can be harmful to humans. Acute inhalation of high levels of chlorine results in the death of airway epithelial cells and can lead to persistent adverse effects on respiratory health, including airway remodeling and hyperreactivity. We previously developed a mouse chlorine exposure model in which animals developed inflammation and fibrosis in large airways. In the present study, examination by laser capture microdissection of developing fibroproliferative lesions in FVB/NJ mice exposed to 240 ppm-h chlorine revealed upregulation of genes related to macrophage function. Treatment of chlorine-exposed mice with the corticosteroid drug budesonide daily for 7 days (30-90 μg/mouse i.m.) starting 1 h after exposure prevented the influx of M2 macrophages and the development of airway fibrosis and hyperreactivity. In chlorine-exposed, budesonide-treated mice 7 days after exposure, large airways lacking fibrosis contained extensive denuded areas indicative of a poorly repaired epithelium. Damaged or poorly repaired epithelium has been considered a trigger for fibrogenesis, but the results of this study suggest that inflammation is the ultimate driver of fibrosis in our model. Examination at later times following 7-day budesonide treatment showed continued absence of fibrosis after cessation of treatment and regrowth of a poorly differentiated airway epithelium by 14 days after exposure. Delay in the start of budesonide treatment for up to 2 days still resulted in inhibition of airway fibrosis. Our results show the therapeutic potential of budesonide as a countermeasure for inhibiting persistent effects of chlorine inhalation and shed light on mechanisms underlying the initial development of fibrosis following airway injury.

Topics: Acute Lung Injury; Animals; Budesonide; Cell Differentiation; Chlorine; Disease Models, Animal; Epithelial Cells; Female; Glucocorticoids; Humans; Inflammation; Inhalation Exposure; Laser Capture Microdissection; Mice; Pulmonary Fibrosis; Respiratory Mucosa; Treatment Outcome

Inflammation and cellular senescence (also called inflammaging) are involved in the pathogenesis of premature lung aging, a key driver of chronic obstructive pulmonary disease (COPD). Downregulation of histone deacetylases and FoxO3 expression, activation of the ERK 1/2 pathway and IL-8 increase are hallmarks of lung inflammaging. The effects of Budesonide (BUD), Aclidinium (ACL) and Formoterol (FO) on lung inflammaging are unknown. This study was aimed to assess the effects of BUD, ACL and FO in bronchial epithelial cells exposed to cigarette smoke extract (CSE) by evaluating: a) Expression of TLR4 and survivin and LPS binding by flow cytometry; b) expression of HDAC2, HDAC3, SIRT1 and FoxO3 and activation of the ERK 1/2 pathway by western blot; c) IL-8 mRNA levels and release by Real Time-PCR and ELISA, respectively. Reported results show that CSE increased TLR4 and survivin, LPS binding, ERK 1/2 activation, IL-8 release and mRNA levels but decreased SIRT1, HDAC2, HDAC3 and FoxO3 nuclear expression. Combined therapy with BUD, ACL and FO counteracted the effects of CSE on LPS binding, FoxO3 nuclear expression, ERK 1/2 activation, survivin and IL-8 release and mRNA levels. These findings suggest a new role of combination therapy with BUD, ACL and FO in counteracting inflammaging processes induced by cigarette smoke exposure.

Topics: Bronchi; Budesonide; Cells, Cultured; Cellular Senescence; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Forkhead Box Protein O3; Formoterol Fumarate; Humans; Inflammation; Lipopolysaccharides; Nicotiana; Sirtuin 1; Smoke; Toll-Like Receptor 4; Tropanes

To investigate the protective effects of budesonide against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in a murine model and its underlying mechanism.. Budesonide pretreatment dramatically attenuated pathological injury and reduced pathological scores in mice with ALI. Budesonide pretreatment obviously reduced the numbers of total cells, neutrophils, and macrophages in the BALF of mice with ALI. Additionally, budesonide dramatically reduced TNF-. Suppression of NLRP3 inflammasome activation in mice via budesonide attenuated lung injury induced by LPS in mice with ALI.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Budesonide; Caspase 1; Cytokines; Inflammasomes; Inflammation; Interleukin-1beta; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

Topics: Animals; Budesonide; Infant, Newborn; Inflammation; Lung Injury; Respiration, Artificial; Sheep; Surface-Active Agents

In this study, we developed pH-triggered surface charge-reversal lipid nanoparticles (LNPs), loaded with budesonide, which could precisely deliver the drug to inflamed colon segments for the treatment of ulcerative colitis. Polyethyleneimine (PEI) was used to render LNPs cationic (PEI-LNPs), and Eudragit® S100 (ES) was coated on PEI-LNPs to obtain pH-triggered charge-reversal LNPs (ES-PEI-LNPs). ES coating avoided a burst drug release under acidic conditions mimicking the stomach and early small intestine environments and showed a sustained release in the colon. The surface charge of ES-PEI-LNPs switched from negative to positive under colonic conditions owing to pH-triggered removal of the ES coating. Bioimaging of the mouse gastrointestinal tract and confocal analysis of colon tissues revealed that ES-PEI-LNPs selectively accumulated in an inflamed colon. Furthermore, ES-PEI-LNPs mitigated experimental colitis in mice. These results suggest that the pH-triggered charge-reversal LNPs could be a promising drug carrier for ulcerative colitis therapy and other colon-targeted treatments.

Topics: Animals; Anti-Inflammatory Agents; Budesonide; Colitis; Dextran Sulfate; Drug Delivery Systems; Hydrogen-Ion Concentration; Inflammation; Lipopeptides; Mice; Nanoparticles; Polyethyleneimine; Polymethacrylic Acids

Human rhinovirus (HRV) infection causes more than 80% of all common colds and is associated with severe complications in patients with asthma and chronic obstructive pulmonary disease. To identify antiviral drug against HRV infection, we screened 800 FDA-approved drugs and found budesonide as one of the possible drug candidates. Budesonide is a corticosteroid, which is commonly used to prevent exacerbation of asthma and symptoms of common cold. Budesonide specifically protects host cells from cytotoxicity following HRV infection, which depend on the expression of glucocorticoid receptor. Intranasal administration of budesonide lowered the pulmonary HRV load and the levels of IL-1β cytokine leading to decreased lung inflammation. Budesonide regulates IL-1β production following HRV infection independent of inflammasome activation. Instead, budesonide induces mitochondrial reactive oxygen species followed by activation of autophagy. Further, the inhibition of autophagy following chloroquine or bafilomycin A1 treatment reduced the anti-viral effect of budesonide against HRV, suggesting that the antiviral activity of budesonide was mediated via autophagy. The results suggest that budesonide represents a promising antiviral and anti-inflammatory drug candidate for the treatment of human rhinovirus infection.

Topics: Administration, Intranasal; Animals; Anti-Inflammatory Agents; Antiviral Agents; Autophagy; Budesonide; Cell Line; Disease Models, Animal; Female; Humans; Inflammation; Interleukin-1beta; Lung; Mice; Mitochondria; Picornaviridae Infections; Reactive Oxygen Species; Rhinovirus; Viral Load; Virus Replication

Topics: Algorithms; Anti-Inflammatory Agents; Budesonide; Colitis, Ulcerative; Double-Blind Method; Humans; Inflammation

The experimental model of combined allergic rhinitis and asthma syndrome (CARAS) has shown that CpG oligodeoxynucleotides (CpG-ODNs) are potential inhibitors of type 2 helper cell-driven inflammatory responses. Currently available CpG-ODNs modestly inhibit allergic responses in CARAS, while a combination strategy for upper airway treatment by co-administration of CpG-ODNs and glucocorticoids may show good efficacy. This study aimed to assess the therapeutic effects of CpG-ODNs combined with budesonide (BUD) on upper and lower-airway inflammation and remodeling in mice with CARAS induced by chronic exposure to ovalbumin (OVA), exploring the possible underlying molecular mechanisms. A BALB/c mouse model of chronic CARAS was established by systemic sensitization and repeated challenge with OVA. Treatment with CpG-ODNs or BUD by intranasal administration was started 1 h after OVA challenge. Then, nasal mucosa and lung tissues were fixed and stained for pathologic analysis. The resulting immunologic variables and TSLP-DC-OX40L axis parameters were evaluated. Both CpG-ODNs and BUD intranasal administration are effective on reducing Th2-type airway inflammation and tissue remodeling. Co-administration of CpG-ODNs and BUD was more effective than each monotherapy in attenuating upper and lower-airway inflammation as well as airway remodeling in chronic CARAS. Notably, combination of CpG-ODNs with BUD modulated the TSLP-DC-OX40L axis, as demonstrated by decreased TSLP production in the nose and lung, alongside decreased TSLPR and OX40L in DC. Intranasal co-administration of CpG-ODNs and BUD synergistically alleviates airway inflammation and tissue remodeling in experimental chronic CARAS, through shared cellular pathways, as a potent antagonist of the TSLP-DC-OX40L axis.

Topics: Airway Remodeling; Animals; Asthma; Budesonide; Cytokines; Drug Synergism; Inflammation; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides; Ovalbumin; OX40 Ligand; Rhinitis, Allergic; Thymic Stromal Lymphopoietin; Tumor Necrosis Factor Inhibitors

The importance of developing new animal models to assess the pathogenesis of glucocorticoid (GC)-insensitive asthma has been stressed. Because of the asthma-prone background of A/J mice, we hypothesized that asthma changes in these animals would be or become resistant to GCs under repeated exposures to an allergen. A/J mice were challenged with OVA for 2 or 4 consecutive d, starting on day 19 postsensitization. Oral dexamethasone or inhaled budesonide were given 1 h before challenge, and analyses were done 24 h after the last challenge. Airway hyperreactivity, leukocyte infiltration, tissue remodeling, and cytokine levels as well as phosphorylated GC receptor (p-GCR), p-GATA-3, p-p38, MAPK phosphatase-1 (MKP-1), and GC-induced leucine zipper (GILZ) levels were assessed. A/J mice subjected to two daily consecutive challenges reacted with airway hyperreactivity, subepithelial fibrosis, and marked accumulation of eosinophils in both bronchoalveolar lavage fluid and peribronchial space, all of which were clearly sensitive to dexamethasone and budesonide. Conversely, under four provocations, most of these changes were steroid resistant. A significant reduction in p-GCR/GCR ratio following 4- but not 2-d treatment was observed, as compared with untreated positive control. Accordingly, steroid efficacy to transactivate MKP-1 and GILZ and to downregulate p-p38, p-GATA-3 as well as proinflammatory cytokine levels was also seen after two but not four provocations. In conclusion, we report that repeated allergen exposure causes GC-insensitive asthma in A/J mice in a mechanism associated with decrease in GCR availability and subsequent loss of steroid capacity to modulate pivotal regulatory proteins, such as GATA-3, p-p38, MKP-1, and GILZ.

Topics: Allergens; Animals; Asthma; Biological Availability; Bronchoalveolar Lavage Fluid; Budesonide; Cytokines; Dexamethasone; Disease Models, Animal; Down-Regulation; Eosinophils; Glucocorticoids; Hypersensitivity; Inflammation; Lung; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Receptors, Glucocorticoid; Steroids; Transcriptional Activation

Terbutaline aerosol and budesonide suspension are commonly used in the treatment of bronchial asthma, and budesonide suspension has local high efficiency and anti-inflammatory effects. In this paper, we selected 240 patients with bronchial asthma and randomly divided them into two groups. The experimental group was treated with atomization inhalation of terbutaline, after 5 minutes interval, nebulized inhalation of budesonide was performed. The control group was treated with atomized inhalation of mixed liquid as terbutaline and budesonide. After treatment, the cough scores of the two groups decreased, and the dyspnea score improved significantly compared with that before treatment (P<0.05).After treatment, the levels of IL-6, BNP and CRP were decreased in the two groups. There was a significant difference between the two groups after treatment (P<0.05). The incidence of adverse drug reactions was low. There were 2 cases of panic disorder and 8 cases of pharyngeal discomfort in the experimental group. The results show that the interval medication of terbutaline and budesonide in the treatment of bronchial asthma can achieve better clinical efficacy and can provide reference for clinical treatment. In addition, this method can effectively reduce the level of inflammatory factors in acute asthma patients, thereby reducing the damage of inflammatory factors to the body.

Topics: Administration, Inhalation; Adult; Asthma; Bronchodilator Agents; Budesonide; Female; Glucocorticoids; Humans; Inflammation; Inflammation Mediators; Male; Rehabilitation Nursing; Terbutaline

Patients with more severe chronic obstructive pulmonary disease frequently experience exacerbations and it is estimated that up to 50% of these exacerbations are associated with bacterial infections. The mainstay treatment for these infection-related exacerbations constitutes the administration of glucocorticoids, alone or in combination with antibiotics. A recent line of evidence demonstrates that many hormones including the steroid beclomethasone can also directly affect bacterial growth, virulence, and antibiotic resistance. The effect of these regimens on the release of potentially virulent and toxic membrane vesicles (MVs) is at present unclear. In this study, we determined the effect of several pharmacological agents on MVs release by and bacterial growth of common respiratory pathogens. We found that neither the release of MVs nor the bacterial growth was affected by the glucocorticoids budesonide and fluticasone. The macrolide antibiotic azithromycin only inhibited the growth of Moraxella catarrhalis but no effects were observed on bacterial MV release at a concentration that is achieved locally in the epithelial lining on administration. The macrophage pro-inflammatory response to MVs was significantly reduced after treatment with budesonide and fluticasone but not by azithromycin treatment. Our findings suggest that these glucocorticoids may have a positive effect on infection-related inflammation although the bacterial growth and MV release remained unaffected.

Topics: Anti-Bacterial Agents; Azithromycin; Bacteria; Bacterial Infections; Beclomethasone; Budesonide; Cell Line; Cell-Derived Microparticles; Fluticasone; Glucocorticoids; Humans; Inflammation; Macrophages

Budesonide (BUD), a poorly soluble anti-inflammatory drug, is used to treat patients suffering from asthma and COPD (Chronic Obstructive Pulmonary Disease). Hydroxypropyl-β-cyclodextrin (HPβCD), a biocompatible cyclodextrin known to interact with cholesterol, is used as a drug-solubilizing agent in pharmaceutical formulations. Budesonide administered as an inclusion complex within HPβCD (BUD:HPβCD) required a quarter of the nominal dose of the suspension formulation and significantly reduced neutrophil-induced inflammation in a COPD mouse model exceeding the effect of each molecule administered individually. This suggests the role of lipid domains enriched in cholesterol for inflammatory signaling activation. In this context, we investigated the effect of BUD:HPβCD on the biophysical properties of membrane lipids. On cellular models (A549, lung epithelial cells), BUD:HPβCD extracted cholesterol similarly to HPβCD. On large unilamellar vesicles (LUVs), by using the fluorescent probes diphenylhexatriene (DPH) and calcein, we demonstrated an increase in membrane fluidity and permeability induced by BUD:HPβCD in vesicles containing cholesterol. On giant unilamellar vesicles (GUVs) and lipid monolayers, BUD:HPβCD induced the disruption of cholesterol-enriched raft-like liquid ordered domains as well as changes in lipid packing and lipid desorption from the cholesterol monolayers, respectively. Except for membrane fluidity, all these effects were enhanced when HPβCD was complexed with budesonide as compared with HPβCD. Since cholesterol-enriched domains have been linked to membrane signaling including pathways involved in inflammation processes, we hypothesized the effects of BUD:HPβCD could be partly mediated by changes in the biophysical properties of cholesterol-enriched domains.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; A549 Cells; Biophysics; Budesonide; Cell Line, Tumor; Cholesterol; Cyclodextrins; Diphenylhexatriene; Fluoresceins; Fluorescent Dyes; Humans; Inflammation; Membrane Fluidity; Membrane Lipids; Membranes; Permeability; Signal Transduction; Unilamellar Liposomes

T cells are key players in the chronic intestinal inflammation that characterises Crohn's disease. Here we aim to map the intestinal T-cell receptor [TCR] repertoire in patients with Crohn's disease, using next-generation sequencing technology to examine the clonality of the T-cell compartment in relation to mucosal inflammation and response to therapy.. Biopsies were taken from endoscopically inflamed and uninflamed ileum and colon of 19 patients with Crohn's disease. From this cohort, additional biopsies were taken after 8 weeks of remission induction therapy from eight responders and eight non-responders. Control biopsies from 11 patients without inflammatory bowel disease [IBD] were included. The TCRβ repertoire was analysed by next-generation sequencing of biopsy RNA.. Both in Crohn's disease patients and in non-IBD controls, a broad intestinal T-cell repertoire was found, with a considerable part consisting of expanded clones. Clones in Crohn's disease were more expanded [p = 0.008], with the largest clones representing up to as much as 58% of the total repertoire. There was a substantial overlap of the repertoire between inflamed and uninflamed tissue and between ileum and colon. Following therapy, responders showed larger changes in the T-cell repertoire than non-responders, although a considerable part of the repertoire remained unchanged in both groups.. The intestinal T-cell repertoire distribution in Crohn's disease is different from that in the normal gut, containing profoundly expanded T-cell clones that take up a large part of the repertoire. The T-cell repertoire is fairly stable regardless of endoscopic mucosal inflammation or response to therapy.

Topics: Adalimumab; Adult; Anti-Inflammatory Agents; Biopsy; Budesonide; C-Reactive Protein; Case-Control Studies; Clone Cells; Colon; Crohn Disease; Female; Gastrointestinal Agents; Humans; Ileum; Inflammation; Infliximab; Male; Middle Aged; Receptors, Antigen, T-Cell; Severity of Illness Index; T-Lymphocytes; Young Adult

Inflammation drives asthma and atherosclerosis. Clinical studies suggest that asthmatic patients have a high risk of atherosclerosis. Yet this hypothesis remains uncertain, given that Th2 imbalance causes asthma whereas Th1 immunity promotes atherosclerosis. In this study, chronic allergic lung inflammation (ALI) was induced in mice by ovalbumin sensitization and challenge. Acute ALI was induced in mice by ovalbumin and aluminum sensitization and ovalbumin challenge. Atherosclerosis was produced in apolipoprotein E-deficient (Apoe(-/-)) mice with a Western diet. When chronic ALI and atherosclerosis were produced simultaneously, ALI increased atherosclerotic lesion size, lesion inflammatory cell content, elastin fragmentation, smooth muscle cell (SMC) loss, lesion cell proliferation, and apoptosis. Production of acute ALI before atherogenesis did not affect lesion size, but increased atherosclerotic lesion CD4(+) T cells, lesion SMC loss, angiogenesis, and apoptosis. Production of acute ALI after atherogenesis also did not change atherosclerotic lesion area, but increased lesion elastin fragmentation, cell proliferation, and apoptosis. In mice with chronic ALI and diet-induced atherosclerosis, daily inhalation of a mast cell inhibitor or corticosteroid significantly reduced atherosclerotic lesion T-cell and mast cell contents, SMC loss, angiogenesis, and cell proliferation and apoptosis, although these drugs did not affect lesion area, compared with those that received vehicle treatment. In conclusion, both chronic and acute ALI promote atherogenesis or aortic lesion pathology, regardless whether ALI occurred before, after, or at the same time as atherogenesis. Antiasthmatic medication can efficiently mitigate atherosclerotic lesion pathology.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Budesonide; Chronic Disease; Disease Progression; Glucocorticoids; Hypersensitivity; Inflammation; Ketotifen; Male; Mast Cells; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Pneumonia

Serum periostin is a potential biomarker of response to therapies that target type 2 inflammation in asthma. The objectives of this study were to describe: 1) the distribution of serum periostin levels in adults with symptomatic airflow obstruction; 2) its relationship with other variables, including type 2 biomarkers; and 3) the effect of inhaled corticosteroids on periostin levels.Serum periostin levels were measured in a cross-sectional study exploring phenotypes and biomarkers in 386 patients aged 18-75 years who reported wheeze and breathlessness in the past 12 months. In 49 ICS-naïve patients, periostin levels were measured again after 12 weeks of budesonide (800 μg·day(-1)).The distribution of serum periostin levels was right skewed (mean±sd 57.3±18.6 ng·mL(-1), median (interquartile range) 54.0 (45.1-65.6) ng·mL(-1), range 15.0-164.7 ng·mL(-1)). Periostin was positively associated with exhaled nitric oxide (Spearman's rho=0.22, p<0.001), blood eosinophil count (Spearman's rho=0.21, p<0.001), and total IgE (Spearman's rho=0.14, p=0.007). The Hodges-Lehmann estimator (95% CI) of change in periostin level after ICS therapy was -4.8 (-6.7- -3.2) ng·mL(-1) (p<0.001).These findings provide data on the distribution of serum periostin in adults with symptomatic airflow obstruction, the weak associations between periostin and other type 2 markers, and the reduction in periostin with inhaled corticosteroid therapy.

Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Asthma; Budesonide; Cell Adhesion Molecules; Cross-Sectional Studies; Eosinophils; Exhalation; Female; Humans; Inflammation; Lung Diseases, Obstructive; Male; Middle Aged; New Zealand; Nitric Oxide; Respiratory Function Tests; Respiratory Sounds; Risk Factors; Surveys and Questionnaires; Young Adult

Meconium aspiration syndrome (MAS) is a serious condition, which can be treated with exogenous surfactant and mechanical ventilation. However, meconium-induced inflammation, lung edema and oxidative damage may inactivate delivered surfactant and thereby reduce effectiveness of the therapy. As we presumed that addition of anti-inflammatory agent into the surfactant may alleviate inflammation and enhance efficiency of the therapy, this study was performed to evaluate effects of surfactant therapy enriched with budesonide versus surfactant-only therapy on markers of oxidative stress in experimental model of MAS. Meconium suspension (25 mg/ml, 4 ml/kg) was instilled into the trachea of young rabbits, whereas one group of animals received saline instead of meconium (C group, n = 6). In meconium-instilled animals, respiratory failure developed within 30 min. Then, meconium-instilled animals were divided into 3 groups according to therapy (n = 6 each): with surfactant therapy (M + S group), with surfactant + budesonide therapy (M + S + B), and without therapy (M group). Surfactant therapy consisted of two bronchoalveolar lavages (BAL) with diluted surfactant (Curosurf, 5 mg phospholipids/ml, 10 ml/kg) followed by undiluted surfactant (100 mg phospholipids/kg), which was in M + S + B group enriched with budesonide (Pulmicort, 0.5 mg/ml). Animals were oxygen-ventilated for additional 5 hours. At the end of experiment, blood sample was taken for differential white blood cell (WBC) count. After euthanizing animals, left lung was saline-lavaged and cell differential in BAL was determined. Oxidative damage, i.e. oxidation of lipids (thiobarbituric acid reactive substance (TBARS) and conjugated dienes) and proteins (dityrosine and lysine-lipoperoxidation products) was estimated in lung homogenate and isolated mitochondria. Total antioxidant capacity was evaluated in lung homogenate and plasma. Meconium instillation increased transmigration of neutrophils and production of free radicals compared to controls (P < 0.05). Surfactant therapy, but particularly combined surfactant + budesonide therapy reduced markers of oxidative stress versus untreated animals (P < 0.05). In conclusion, budesonide added into surfactant enhanced effect of therapy on oxidative damage of the lung.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Budesonide; Disease Models, Animal; Female; Free Radicals; Inflammation; Lung; Lung Injury; Male; Meconium; Meconium Aspiration Syndrome; Neutrophils; Oxidative Stress; Pulmonary Edema; Pulmonary Surfactants; Rabbits; Trachea

To develop a nanoparticulate drug carrier for targeting of the inflamed intestinal mucosa, amphiphilic hyaluronic acid (HA) conjugates were synthesized, which could form self-assembled nanoparticles (NPs) in aqueous solution and budesonide (BDS) was loaded into the HANPs. Their particle sizes were in the range of 177 to 293nm with negative surface charge. The model of inflammatory CACO-2 cells was utilized to investigate the therapeutic potential of budesonide loaded HA nanocarriers. The highest expression of CD44 receptors was found on inflamed Caco-2 cells, as determined by flow cytometry. FITC-labeled HANPs revealed greater uptake in inflamed CACO-2 cells compared to untreated CACO-2 and CD44-negative cell lines, NIH3T3. BDS loaded HANPs displayed almost no toxicity indicating HANPs are excellent biocompatible nano-carriers. BDS loaded HANPs demonstrated higher anti-inflammatory effect on IL-8 and TNF-α secretion in inflamed cell model compared to the same dose of free drug. These results revealed the promising potential of HA nanoparticles as a targeted drug delivery system for IBD treatment.

Topics: Animals; Anti-Inflammatory Agents; Biological Transport; Budesonide; Caco-2 Cells; Drug Carriers; Drug Liberation; Gene Expression Regulation; Humans; Hyaluronan Receptors; Hyaluronic Acid; Hydrophobic and Hydrophilic Interactions; Inflammation; Intestinal Mucosa; Mice; Nanoparticles; NIH 3T3 Cells

The aim of this study was to determinate bronchodilator, antitussive, and ciliomodulatory activity of inhaled combination therapy with budesonide and salmeterol, and to correlate the results with the anti-inflammatory effect. The experiments were performed using two models of allergic inflammation (21 and 28 days long sensitization with ovalbumine) in guinea pigs. The animals were treated daily by aerosols of budesonide (1 mM), salmeterol (0.17 mM), and a half-dose combination of the two drugs. Antitussive and bronchodilator activities were evaluated in vivo. The ciliary beat frequency (CBF) was assessed in vitro in tracheal brushed samples, and inflammatory cytokines (IL-4, IL-5, IL-13, GM-CSF, and TNF-α) were determined in bronchoalveolar lavage fluid (BALF). We found that the combination therapy significantly decreased the number of cough efforts, airway reactivity, and the level of inflammatory cytokines in both models of allergic asthma. Three weeks long sensitization led to an increase in CBF and all three therapeutic approaches have shown a ciliostimulatory effect in order: salmeterol < budesonid < combination therapy. Four weeks long ovalbumine sensitization, on the other hand, decreased the CBF, increased IL-5, and decreased IL-13. In this case, only the combination therapy was able to stimulate the CBF. We conclude that a half-dose combination therapy of budesonide and salmeterol shows comparable antitussive, bronchodilator, and the anti-inflammatory effect to a full dose therapy with budesonide alone, but had a more pronounced stimulatory effect on the CBF.

Topics: Animals; Asthma; Bronchodilator Agents; Budesonide; Cilia; Cough; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Guinea Pigs; Inflammation; Male; Ovalbumin; Salmeterol Xinafoate

Topics: Acute Lung Injury; Adrenal Cortex Hormones; Animals; Apoptosis; Biomarkers; Bronchoalveolar Lavage Fluid; Budesonide; Caspase 3; Disease Models, Animal; Edema; Epithelial Cells; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Lung; Oxidative Stress; Oxygen; Rabbits; Tumor Necrosis Factor-alpha; Ventilation

To investigate the influence of budesonide on animal model of minimal persistent inflammation (MPI) of allergic rhinitis in rats and to investigate the changes of interleukin-12 (IL-12) in nasal mucosa.. Sixty Sprague-Dawley (SD) rats were randomly divided into four groups: group A (allergic rhinitis group), B (experimental group), C (MPI model group) and D (bland group) respectively, with fifteen animals in each group. Rats from group A,B and C were sensitized intraperitoneally by injection of suspension of ovalbumin (OVA) and aluminum hydroxide in 0.9% physiological saline. Then, repeated local booster sensitization with different concentration of OVA suspension (1% and 0.01%) or physiological saline into the nasal cavity of those rats were performed. For group D, physiological saline was used only. From 36th day, group B were given budesonide treatment for three weeks. A, C and D group were given normal saline nasal spray. Symptoms (sneezing) of rats after antigen challenge were observed and the infiltration of eosinophils (EOS) together with the expression of intercellular adhesion molecule 1 (ICAM-1) and IL-12 in the nasal epithelial cells were also examined.. When challenged with 1% OVA, the sneezing number of rats in group B was increased markedly than that in group D (P < 0.05). However, there was no difference between group B, A and C (P > 0.05). When challenged with 0.01% OVA and given budesonide, the symptom of sneezing almost disappeared in group B just like that in group D and there was no difference between the two groups (P > 0.05). Besides, there was still more EOS infiltrated in the nasal mucosa of rats in group C than that in group D (P < 0.05). There was no expression of ICAM-1 in nasal epithelium of rats in group D, nevertheless, ICAM-1 was found mildly expressed in group C. IL-12 expression was significantly increased compared with group A and group C, and was no significantly difference compared with bland group (P > 0.05).. Budesonide significantly inhibited the late reaction of animal model of minimal persistent inflammation (MPI) of allergic rhinitis in rats and increase the expression of IL-12 in MPI model.

Topics: Allergens; Animals; Budesonide; Disease Models, Animal; Eosinophils; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-12; Leukocyte Count; Nasal Mucosa; Ovalbumin; Rats; Rats, Sprague-Dawley; Rhinitis, Allergic

Lymphocytic colitis is a chronic inflammatory disease affecting the bowel. The clinical course of lymphocytic colitis is believed to be benign with watery diarrhoea. We report herein what is, to the best of our knowledge, the first case of lymphocytic colitis complicated by a terminal ileal mass. A 23-year-old man presented with diarrhoea. Blind biopsies of samples taken from the terminal ileum, caecum and ascending colon showed features of lymphocytic colitis. He declined treatment with budesonide or 5-aminosalicylates. He presented 14 months later with pain over the right lumbar region and nausea. Computed tomographic enteroclysis showed a focal soft tissue enhancing mass at the terminal ileum. Excision of the soft tissue mass revealed that it was reactive nodular lymphoid hyperplasia with fibrous granulation tissue. In conclusion, an untreated lymphocytic colitis may result in the formation of an inflammatory mass lesion.

Topics: Biopsy; Budesonide; Cecum; Colitis, Lymphocytic; Colonoscopy; Diarrhea; Fibrosis; Granulation Tissue; Humans; Hyperplasia; Ileum; Inflammation; Intestinal Mucosa; Male; Nausea; Tomography; Treatment Outcome; Young Adult

To explore the role of transient receptor potential canonical 1 (TRPC1) in airway remodeling and the effect of budesonide intervention on its expression in the lungs of guinea pigs with ovalbumin-induced asthma.. Fifty male guinea pigs were randomized into 5 equal groups, including a blank control group, ovalbumin group, ovalbumin+TRPC1 siRNA group, ovalbumin+luciferase siRNA group, and ovalbumin+budesonide group. After corresponding treatments, bronchoalveolar lavage was collected from the guinea pigs for eosinophils analysis and detection of IL-5 and IL-13 levels using ELISA. The lung tissues were stained with HE and Masson's trichrome to observe the bronchial wall thickness, smooth muscle hypertrophy, subepithelial collagen deposition, and lung inflammations. Immunohistochemistry and real-time quantitative PCR were performed to detect TRPC1 protein and mRNA expressions in the lungs, respectively.. The guinea pig models of ovalbumin-induced asthma showed significantly increased thickness of the bronchial wall, smooth muscle hypertrophy, collagen deposition and inflammatory cell infiltration, but these pathologies were obviously alleviated by treatment with TRPC1 siRNA or budesonide (P/0.05). Immunohistochemstry showed that TRPC1 protein was distributed mainly on the cell membrane and in the nuclei of the basal cells or columnar epithelial cells.. The up-regulated expression of TRPC1 ion channel is closely associated with the occurrence and progression of airway remodeling and chronic airway inflammation in asthma. Budesonide can partially suppress airway remodeling and inflammation by regulating the expression of TRPC1.

Topics: Airway Remodeling; Animals; Asthma; Bronchi; Budesonide; Disease Models, Animal; Guinea Pigs; Inflammation; Interleukin-13; Interleukin-5; Leukocyte Count; Lung; Male; Ovalbumin; TRPC Cation Channels

Interleukin-1 beta (IL-1β) plays pivotal roles in the progression of allergic airway inflammation. This study aims to determine whether the blockade of IL-1β can inhibit airway inflammation in guinea pigs with allergic asthma induced by the inhalation of aerosolized ovalbumin (OVA).. Healthy guinea pigs treated with saline were used as normal controls (group C). The guinea pigs with allergic asthma induced by the inhalation of aerosolized OVA were randomly divided into three groups: (1) the M group containing negative control animals treated with saline; (2) the Z1 group containing animals treated by the inhalation of atomized 0.1% anti-IL-1β immunoglobulin yolk (IgY); and (3) the Z2 group containing positive control animals that were treated with budesonide. The inflammatory cells in the peripheral blood (PB) and bronchoalveolar lavage fluid (BALF) were evaluated using methylene blue and eosin staining. Cytokine concentrations were measured using an enzyme-linked immunosorbent assay. Pulmonary sections were examined using hematoxylin-eosin staining.. Allergic inflammation and damage to the pulmonary tissues were decreased in the Z1 group compared to the M group. Eosinophils and neutrophils in the PB and BALF were significantly decreased in the Z1 group compared to the M group (P<0.05). Treatment with anti-IL-1β IgY significantly reduced the levels of IL-1β, IL-4, IL-8, IL-13, TNF-α, TGF-β1 and IgE in the BALF (P<0.05).. The inhalation of aerosolized anti-IL-1β IgY inhibits pathological responses in the pulmonary tissues of guinea pigs with allergic asthma. The inhibitory activity may be due to the decrease in the numbers of eosinophils and neutrophils and the reduced levels of inflammatory cytokines and IgE in the PB and BALF.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Budesonide; Cytokines; Disease Models, Animal; Eosinophils; Guinea Pigs; Immunoglobulin E; Immunoglobulins; Inflammation; Interleukin-1beta; Male; Neutrophils; Ovalbumin

Th17-mediated neutrophilic airway inflammation has been implicated in decreased response to glucocorticoids in asthma. We aimed to investigate the effect of glucocorticoids on the airway epithelial release of the neutrophilic and Th17-cell chemoattractant CCL20. We studied CCL20 and CXCL8 sputum levels in asthmatic subjects using inhaled glucocorticoids or not, and the effect of budesonide on CCL20 and CXCL8 production in primary bronchial epithelial cells. The mechanism behind the effect of budesonide-induced CCL20 production was studied in 16HBE14o- cells using inhibitors for the glucocorticoid receptor, intracellular pathways and metalloproteases. We observed higher levels of CCL20, but not CXCL8, in the sputum of asthmatics who used inhaled glucocorticoids. CCL20 levels correlated with inhaled glucocorticoid dose and sputum neutrophils. Budesonide increased tumour necrosis factor (TNF)-α-induced CCL20 by primary bronchial epithelium, while CXCL8 was suppressed. In 16HBE14o- cells, similar effects were observed at the CCL20 protein and mRNA levels, indicating transcriptional regulation. Although TNF-α-induced CCL20 release was dependent on the ERK, p38 and STAT3 pathways, the increase by budesonide was not. Inhibition of glucocorticoid receptor or ADAM17 abrogated the budesonide-induced increase in CCL20 levels. We show that glucocorticoids enhance CCL20 production by bronchial epithelium, which may constitute a novel mechanism in Th17-mediated glucocorticoid-insensitive inflammation in asthma.

Topics: ADAM Proteins; ADAM17 Protein; Adult; Aged; Asthma; Budesonide; Cells, Cultured; Chemokine CCL20; Epithelial Cells; Epithelium; Extracellular Signal-Regulated MAP Kinases; Female; Glucocorticoids; Humans; Inflammation; Interleukin-8; Male; Metalloproteases; Middle Aged; Neutrophils; Receptors, Glucocorticoid; Sputum; STAT3 Transcription Factor; Th17 Cells; Tumor Necrosis Factor-alpha

The challenge for the treatment of inflammatory bowel disease (IBD) is the delivery of the drug to the site of inflammation. Because nanoparticles have the ability to accumulate in inflamed regions, the aim of the present study was to evaluate nanostructured lipid carriers (NLCs) as nanoparticulate drug delivery systems for the treatment of IBD. Budesonide (BDS) was chosen as a candidate anti-inflammatory drug. BDS-loaded NLCs (BDS-NLC) produced by high-pressure homogenization had a size of 200 nm and a negative zeta potential. BDS-NLCs reduced the TNF-α secretion by activated macrophages (J774 cells). BDS-NLCs were more active in a murine model of dextran sulfate-induced colitis when compared with Blank-NLCs or a BDS suspension: BDS-NLCs decreased neutrophil infiltration, decreased the levels of the pro-inflammatory cytokines IL-1β and TNF-α in the colon and improved the histological scores of the colons. These data suggest that NLCs could be a promising alternative to polymeric nanoparticles as a targeted drug delivery system for IBD treatment.

Topics: Animals; Anti-Inflammatory Agents; Budesonide; Cell Line; Colitis; Colon; Dextran Sulfate; Drug Carriers; Female; Inflammation; Interleukin-1beta; Lipids; Mice; Mice, Inbred C57BL; Nanostructures; Peroxidase; Tumor Necrosis Factor-alpha

Oral budesonide has been proven effective in short- and long-term treatment of collagenous colitis; however, symptom relapse frequently occurs after drug withdrawal. The aim of this study was to identify the risk factors for symptom relapse in patients with collagenous colitis after withdrawal of short-term budesonide therapy.. One hundred twenty-three patients from 4 randomized controlled studies who achieved clinical remission after short-term treatment with budesonide (9 mg/d) were analyzed, including 40 patients receiving subsequent budesonide maintenance therapy (6 mg/d) for 6 months and 83 patients without active maintenance treatment. Variables available for analysis were age, sex, baseline stool frequency, duration of diarrhea, collagenous band thickness, and lamina propria inflammation. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated by Cox proportional hazard model.. The overall symptom relapse rate was 61%. By multivariate analysis, a baseline stool frequency >5 per day (HR, 3.95; 95% CI, 1.08-14.39), history of diarrhea >12 months (HR, 1.77; 95% CI, 1.04-3.03), and the absence of budesonide maintenance therapy (HR, 2.71; 95% CI, 1.37-5.38) were associated with symptom relapse. The time to relapse was shorter in patients with a baseline stool frequency >5 per day (56 versus 199 d, P = 0.024), as in those with history of diarrhea >12 months (56 versus 220 d, P = 0.009). Budesonide maintenance therapy delayed the time to relapse (56 versus 207 d, P = 0.005).. Our data demonstrate that a high stool frequency at baseline and a long duration of diarrhea are risk factors for symptom relapse in collagenous colitis, whereas budesonide maintenance therapy is a protective factor against symptom relapse.

Topics: Anti-Inflammatory Agents; Budesonide; Colitis, Collagenous; Diarrhea; Female; Follow-Up Studies; Humans; Inflammation; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Substance Withdrawal Syndrome

Although CD23-dependent transcytosis of IgE and IgE-derived immune complexes across respiratory epithelial cells is likely to play a pivotal role in the initiation and development of airway allergic inflammation, there is currently a lack of physiological support for this phenomena to suggest that the targeting of CD23 could be used as a means of therapeutic intervention. The present study was designed to detect the CD23 expression in the nasal mucosa of allergic rhinitis (AR) murine model by immunohistochemistry and western blotting, and to investigate whether intranasal anti-CD23 treatment could inhibit allergen-induced upper airway inflammation in the AR model. This is the first report to show that CD23 was constitutively expressed in murine nasal epithelial cells, and its expression was significantly up-regulated in the AR murine model. In vivo, the up-regulation of CD23 expression was correlated with increased serum IL-4 levels. Following intranasal anti-CD23 treatment, nasal symptoms were alleviated and histopathologic examination showed a significant decrease in eosinophilic infiltration. Meanwhile, ELISA analysis showed levels of serum leukotriene C4 (LTC4), eosinophil cation protein (ECP), ovalbumin (OVA)-specific IgE and IL-4 also significantly decreased, as were LTC4 and OVA-specific IgE in the nasal lavage fluid. Furthermore, Western blotting analysis showed that ECP expression in the nasal mucosa was down-regulated. Finally, flow cytometric analysis revealed anti-CD23 treatment inhibited Th2 cell responses. These results indicate that intranasal anti-CD23 treatment can reduce allergic responses in a murine model of allergic rhinitis.

Topics: Administration, Intranasal; Allergens; Animals; Budesonide; Disease Models, Animal; Down-Regulation; Eosinophil Cationic Protein; Eosinophils; Epithelial Cells; Female; Hypersensitivity; Immunoglobulin E; Inflammation; Interleukin-4; Leukotriene C4; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Random Allocation; Receptors, IgE; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Th2 Cells; Up-Regulation

Glucocorticoids are widely regarded as the most effective treatment for asthma. However, the direct impact of glucocorticoids on the innate immune system and antibacterial host defense during asthma remain unclear. Understanding the mechanisms underlying this process is critical to the clinical application of glucocorticoids for asthma therapy. After sensitization and challenge with ovalbumin (OVA), BALB/c mice were treated with inhaled budesonide and infected with Pseudomonas aeruginosa (P. aeruginosa). The number of viable bacteria in enflamed lungs was evaluated, and levels of interleukin-4 (IL-4) and interferon-γ (IFN-γ) in serum were measured. A lung epithelial cell line was pretreated with budesonide. Levels of cathelicidin-related antimicrobial peptide (CRAMP) were measured by immunohistochemistry and western blot analysis. Intracellular bacteria were observed in lung epithelial cells.. Inhaled budesonide enhanced lung infection in allergic mice exposed to P. aeruginosa and increased the number of viable bacteria in lung tissue. Higher levels of IL-4 and lower levels of IFN-γ were observed in the serum. Budesonide decreased the expression of CRAMP, increased the number of internalized P. aeruginosa in OVA-challenged mice and in lung epithelial cell lines. These data indicate that inhaled budesonide can suppress pulmonary antibacterial host defense by down-regulating CRAMP in allergic inflammation mice and in cells in vitro.. Inhaled budesonide suppressed pulmonary antibacterial host defense in an asthmatic mouse model and in lung epithelium cells in vitro. This effect was dependent on the down-regulation of CRAMP.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Budesonide; Cathelicidins; Colony Count, Microbial; Down-Regulation; Epithelial Cells; Host-Pathogen Interactions; Hypersensitivity; Immunosuppression Therapy; Inflammation; Interferon-gamma; Interleukin-4; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Pseudomonas aeruginosa; Pseudomonas Infections

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder of the lung, and is the fifth leading cause of morbidity worldwide. A novel proinflammatory factor, interleukine-32 (IL-32), is suggested as a risk factor of COPD. Budesonide is widely used for COPD treatment as anti-inflammatory drug. However, the inflammatory inhibition mechanism of budesonide is not fully understood. In this study, we used a rat model with COPD to investigate the effect of budesonide on IL-32 expression in lung tissue. We found that cigarette smoking (CS) strongly induced IL-32 expression in lung tissue, seriously weakened lung function, and damaged pulmonary tissue. Budesonide inhibited the expression of IL-32 in lung tissue. In budesonide-treated rats, we observed no repair of damaged lung tissue but the pulmonary function was partly recovered. To our knowledge, this is the first report that budesonide inhibits the expression of IL-32 in lung tissues, which is strongly induced by CS.

Topics: Animals; Anti-Inflammatory Agents; Budesonide; Inflammation; Interleukins; Lung; Male; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Risk Factors; Smoking

Patients with chronic obstructive pulmonary disease (COPD) respond poorly to corticosteroids. Histone deacetylase-2 (HDAC-2) plays a pivotal role in many cases of steroid insensitivity. The main aim of this study was to restore the smoking-induced reduction in corticosteroid sensitivity by increasing HDAC-2 activity using low-dose theophylline. Rats were exposed to cigarette smoke (CS) and treated with budesonide and two doses of theophylline. Besides the pathologic examination and cell counting in the bronchoalveolar lavage fluid (BALF), the expression of HDAC-2 and CXC chemokine ligand-8 (CXCL-8) were measured. Airway inflammation induced by CS was demonstrated by pathologic changes of lung tissue and increased level of CXCL-8. CS exposure also markedly decreased HDAC-2 expression. Moreover, a negative correlation was found between HDAC-2 activity and a lung destruction index. The index was restored to control levels with inhaled corticosteroid treatment in combination with a low, not a high, dose of theophylline. These results indicate that low-dose theophylline might provide protection from smoke damage and improve the anti-inflammatory effects of steroids by increasing HDAC-2 activity.

Topics: Adrenal Cortex Hormones; Animals; Bronchoalveolar Lavage Fluid; Budesonide; Dose-Response Relationship, Drug; Histone Deacetylase 2; Inflammation; Interleukin-8; Lung; Male; Rats; Rats, Wistar; Smoke; Smoke Inhalation Injury; Smoking; Theophylline

(±)-Praeruptorin A (PA) is a pair of coumarin enantiomers isolated from the root of Peucedanum praeruptorum Dunn (PPD), a common Chinese herbal medicine for the treatment of asthma. Considering its anti-inflammatory, anti-contractile and anti-hyperplasia activities, the effects of PA on airway inflammation and airway remodeling were investigated using a murine model of chronic asthma. Ovalbumin-sensitized BALB/c mice were challenged with ovalbumin to induce asthma every other day on eight successive weeks. PA was administered intragastrically before every ovalbumin challenge. Airway responsiveness was evaluated by a lung function analysis system 48 h after the last ovalbumin challenge. The total and differential leukocytes in bronchoalveolar lavage fluid (BALF) were counted using a hemocytometer and Diff-Quick-stained smears. Lung tissue samples were used for hematoxylin and eosin, periodic acid Schiff, Masson's trichrome and α-SMA immunohistochemistry staining. Levels of cytokines in BALF, immunoglobulin (Ig) E in serum as well as expression of TGF-β1 and Smad proteins in lung tissue were measured by enzyme-linked immunosorbent assay, immunohistochemistry or western blot analysis. Compared with the model group, PA suppressed airway inflammation, airway hyperresponsive and remodeling, reduced levels of IL-4 and IL-13 in BALF, and IgE in serum, inhibited expression of TGF-β1 and pSmad2/3, up-regulated the expression of Smad7 in lung tissue, and also increased the levels of INF-γ in BALF. These results suggested that PA significantly suppressed airway inflammation and airway remodeling induced by ovalbumin challenge, and is a potential candidate for the treatment of asthma.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Asthma; Budesonide; Cell Line; Coumarins; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Immunoglobulin E; Inflammation; Lung; Macrophages; Mice; Mice, Inbred BALB C; Molecular Structure; Smad Proteins; Transforming Growth Factor beta

The recurrent TNBS-colitis model in BALB/c mice has been proposed as a model of Inflammatory Bowel Disease with a shifting pattern of local cytokines with the expression of Th1 cytokines during the early phase, Th17 cytokines during the intermediate phase and Th2 cytokines during late fibrotic stages. In this study, we evaluated the development of pathology in time-in conjunction with genome-wide gene expression in the colons-in response to three weekly intrarectal instillations of TNBS. During this time-frame mice develop colitis with extensive cellular infiltration of (sub)mucosa and mildly to moderately affected crypt architecture. These pathological processes were sensitive to local treatment with budesonide. Gene expression profiling confirmed an acute phase response after each intrarectal TNBS-challenge. In addition, a chronic inflammatory process developed over time particularly evident from a gradual increase in expression of mast cell related genes. The changes in pathological hallmarks were consistent with a temporal expression of mRNA encoding a selection of chemokines. In conclusion, the early stages of the recurrent TNBS-colitis model reflect several aspects of inflammatory bowel disease which are sensitive to immunomodulation.

Topics: Administration, Rectal; Animals; Anti-Inflammatory Agents; Budesonide; Chronic Disease; Colitis; Colon; Cytokines; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation; Immunomodulation; Inflammation; Mice; Mice, Inbred BALB C; Oligonucleotide Array Sequence Analysis; Signal Transduction; Th1-Th2 Balance; Time Factors; Transcriptome; Trinitrobenzenesulfonic Acid

To characterize physical and inflammatory injury that may result from repeated intubation, independent of positive-pressure ventilation; and to determine whether corticosteroids can attenuate injury and or inflammation that may result from repeated intubation.. A 4-hr animal protocol.. All work was done in the animal laboratory at the Alfred I. DuPont Hospital for Children.. Neonatal piglets (2-8 days old; 2.5 ± 0.4 kg) were intubated and randomized to four groups (n = 8 each) to be followed over 4 hrs. Groups were control (not reintubated), injured (reintubated every 0.5 hr), intratracheal pretreatment with 1 mg of nebulized budesonide (intratracheal pretreated), or intravenous pretreatment with 0.3 mg/kg of dexamethasone (intravenous pretreated).. Each pig was sedated for the duration of study and had a 3.5F catheter inserted in the femoral artery for blood sampling and blood pressure measurement every hour. After 4 hrs, each pig was killed, and tissue was harvested for histology and interleukin-6 assays.. Laryngeal tissue interleukin-6 content was greater in the injured group compared with the control group (p < .05). In the intratracheal pretreated group, the interleukin-6 content of laryngeal tissue was greater compared with the control group (p < .05), whereas the intravenous pretreated group was not different from the control group. The reintubation injury resulted in plasma interleukin-6 levels that, compared with control, were greater in the injured and intratracheal pretreated groups (p < .05). Quantitative histology showed that the degree of tracheal injury was higher in injured and intratracheal pretreated groups compared with the control group (p < .05).. Repeated intubation alone results in significant tracheal trauma and systemic inflammation. Intravenous but not inhaled steroids attenuated the injury.

Topics: Airway Obstruction; Analysis of Variance; Animals; Animals, Newborn; Biomarkers; Budesonide; Dexamethasone; Disease Models, Animal; Inflammation; Injury Severity Score; Interleukin-6; Intubation, Intratracheal; Larynx; Random Allocation; Swine

Acute lung injury (ALI) is associated with systemic inflammation and cardiovascular dysfunction. IL-6 is a biomarker of this systemic response and a predictor of cardiovascular events, but its possible causal role is uncertain. Inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) down-regulate the systemic expression of IL-6, but whether they can ameliorate the cardiovascular dysfunction related to ALI is uncertain. We sought to determine whether IL-6 contributes to the cardiovascular dysfunction related to ALI, and whether budesonide/formoterol ameliorates this process. Wild-type mice were pretreated for 3 hours with intratracheal budesonide, formoterol, or both, before LPS was sprayed into their tracheas. IL-6-deficient mice were similarly exposed to LPS. Four hours later, bronchoalveolar lavage fluid (BALF) and serum were collected, and endothelial and cardiac functions were measured, using wire myography of the aortic tissue and echocardiography, respectively. LPS significantly impaired vasodilatory responses to acetylcholine (P < 0.001) and cardiac output (P = 0.002) in wild-type but not IL-6-deficient mice. Intratracheal instillations of exogenous IL-6 into IL-6-deficient mice restored these impairments (vasodilatory responses to acetylcholine, P = 0.005; cardiac output, P = 0.025). Pretreatment with the combination of budesonide and formoterol, but not either alone, ameliorated the vasodilatory responses to acetylcholine (P = 0.018) and cardiac output (P < 0.001). These drugs also attenuated the rise in the systemic expression of IL-6 (P < 0.05) related to LPS. IL-6 contributes to the cardiovascular dysfunction related to LPS, and pretreatment with budesonide/formoterol reduces the systemic expression of IL-6 and improves cardiovascular dysfunction. ICS/LABA may reduce acute cardiovascular events related to ALI.

Topics: Acetylcholine; Acute Lung Injury; Adrenal Cortex Hormones; Animals; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Budesonide; Cardiovascular Diseases; Ethanolamines; Formoterol Fumarate; Inflammation; Interleukin-6; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Vasodilation

Topics: Airway Obstruction; Animals; Animals, Newborn; Biomarkers; Budesonide; Dexamethasone; Disease Models, Animal; Humans; Inflammation; Interleukin-6; Intubation, Intratracheal; Larynx; Randomized Controlled Trials as Topic; Swine

This protocol describes microsphere-based protease assays for use in flow cytometry and high-throughput screening. This platform measures a loss of fluorescence from the surface of a microsphere due to the cleavage of an attached fluorescent protease substrate by a suitable protease enzyme. The assay format can be adapted to any site or protein-specific protease of interest and results can be measured in both real time and as endpoint fluorescence assays on a flow cytometer. Endpoint assays are easily adapted to microplate format for flow cytometry high-throughput analysis and inhibitor screening.

Topics: Animals; Biotinylation; Flow Cytometry; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins; High-Throughput Screening Assays; Humans; Inflammation; Kinetics; Microspheres; Peptide Hydrolases; Peptides; Reproducibility of Results; Temperature

Collagenous colitis (CC) is characterized by chronic watery diarrhea, a macroscopically normal colonic mucosa but typical microscopic inflammation. Chronic mucosal inflammation of the colon and rectum has earlier been associated with altered visceral sensitivity, but anorectal function has never been reported in cases of CC.. Fifteen patients with CC in active phase recorded their symptoms. The severity of inflammation was determined in mucosal biopsies. Anorectal function was assessed and compared with that of 15 healthy volunteers of corresponding age and matched for gender. After 6 weeks of budesonide treatment when the patients were in clinical remission anorectal function was re-assessed.. All patients had inflammation also in rectum. Patients in active phase had, during rectal balloon distension a higher rectal sensory threshold for the feeling of first sensation, compared with controls (P = 0.02). There were no differences in rectal sensory threshold for the feeling of urgency or maximum distension, between patients with CC in active phase and healthy controls. Rectal volume at first sensation was significantly greater in patients than in controls (P = 0.02), but there were no differences at urgency or maximum distension. Twelve of 15 patients completed 6 weeks of budesonide treatment and all went into clinical remission. No differences in anorectal function were measured when patients had active disease, compared with clinical remission.. Collagenous colitis was not associated with rectal hypersensitivity or disturbed anal function despite rectal inflammation. On the contrary, the sensation threshold for light rectal pressure was elevated in patients with active CC.

Topics: Adult; Aged; Anal Canal; Anti-Inflammatory Agents; Budesonide; Catheterization; Colitis, Collagenous; Female; Humans; Inflammation; Male; Manometry; Middle Aged; Rectum; Sensory Thresholds; Severity of Illness Index; Statistics, Nonparametric; Transducers; Treatment Outcome

Asthma is a common disease characterised by reversible airflow obstruction, bronchial hyperresponsiveness and chronic inflammation, which is commonly treated using corticosteroids such as budesonide. MicroRNAs (miRNAs) are a recently identified family of non-protein encoding genes that regulate protein translation by a mechanism entitled RNA interference. Previous studies have shown lung-specific miRNA expression profiles, although their importance in regulating gene expression is unresolved. We determined whether miRNA expression was differentially expressed in mild asthma and the effect of corticosteroid treatment.. We have examined changes in miRNA using a highly sensitive RT-PCR based approach to measure the expression of 227 miRNAs in airway biopsies obtained from normal and mild asthmatic patients. We have also determined whether the anti-inflammatory action of corticosteroids are mediated through miRNAs by determining the profile of miRNA expression in mild asthmatics, before and following 1 month twice daily treatment with inhaled budesonide. Furthermore, we have analysed the expression of miRNAs from individual cell populations from the airway and lung. We found no significant difference in the expression of 227 miRNAs in the airway biopsies obtained from normal and mild asthmatic patients. In addition, despite improved lung function, we found no significant difference in the miRNA expression following one month treatment with the corticosteroid, budesonide. However, analysis of bronchial and alveolar epithelial cells, airway smooth muscle cells, alveolar macrophages and lung fibroblasts demonstrate a miRNA expression profile that is specific to individual cell types and demonstrates the complex cellular heterogeneity within whole tissue samples.. Changes in miRNA expression do not appear to be involved in the development of a mild asthmatic phenotype or in the anti-inflammatory action of the corticosteroid budesonide.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Asthma; Biopsy; Bronchi; Budesonide; Female; Gene Expression Profiling; Humans; Inflammation; Lung; Male; MicroRNAs; Pulmonary Alveoli

Rhinoviruses (RVs) are responsible for the majority of acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations. RVs infect the lower airways and induce the production of pro-inflammatory and remodelling-associated mediators. Budesonide (BUD) and formoterol (FORM) synergize in controlling asthma and COPD exacerbations; however, their effects on virus-induced inflammation and remodelling are less known.. We investigated whether BUD and FORM synergize in suppressing RV-induced inflammation and remodelling in the airways.. In vitro models of RV infection of BEAS-2B and primary normal human bronchial epithelial (NHBE) cells were used. We assessed the effects of individual and combined drugs administered post-infection, at a clinically relevant concentration range (10(-6)-10(-10) m), on the production of CCL5, CXCL10, CXCL8, IL-6 and the remodelling-associated VEGF and bFGF, using ELISA and RT-PCR.. BUD effectively suppressed RV-mediated induction of all mediators studied, in a concentration-dependent manner. FORM alone suppressed the production of CXCL8 and bFGF. The combination of BUD and FORM had concentration-dependent, additive or synergistic effects in the suppression of RV-induced CCL5, CXCL8 and CXCL10 in both cell types as well as VEGF in NHBE only. Combination treatment also resulted in an enhanced suppression of RV-induced IL-6, and CCL5 at the mRNA level as compared with BUD or FORM alone.. BUD and FORM suppress RV-induced chemokines and growth factors in bronchial epithelial cells in a concentration-dependent, synergistic or additive manner. These data further support the combined use of BUD and FORM in asthma and COPD and intensification of this therapy during exacerbations.

Topics: Asthma; Bronchi; Bronchodilator Agents; Budesonide; Chemokine CXCL10; Chemokines; Drug Synergism; Epithelial Cells; Ethanolamines; Fibroblast Growth Factor 2; Formoterol Fumarate; Humans; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Picornaviridae Infections; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Rhinovirus; Vascular Endothelial Growth Factor A

Topics: Animals; Anti-Inflammatory Agents; Asthma; Budesonide; Eosinophils; Inflammation; NF-kappa B; Random Allocation; Rats; Rats, Sprague-Dawley; Respiratory System

Despite the effectiveness of corticosteroids at resolving airway inflammation, they are only moderately effective at attenuating airway hyperresponsiveness (AHR). The extent to which corticosteroids are able to reverse or inhibit the development of sustained AHR is not known. The present study aimed to determine whether budesonide can resolve and or prevent the development of sustained AHR in mice. Mice were chronically exposed to allergen and treated with budesonide either: 1) briefly during the final weeks of exposure to allergen; 2) prolonged concurrently throughout exposure to allergen; or 3) delayed following final exposure to allergen. AHR was assessed 24 h (brief treatment) or 4 weeks (prolonged concurrent and delayed treatments) following final exposure to allergen. Brief budesonide intervention significantly attenuated the inflammation-associated AHR assessed immediately following final exposure to allergen. Similarly, prolonged concurrent budesonide treatment prevented the development of sustained AHR. Delayed budesonide intervention, however, did not resolve sustained AHR. In conclusion, the early introduction and, importantly, the persistence of corticosteroid treatment prevented the development of sustained airway hyperresponsiveness; however, the inability of corticosteroids to reverse established airway dysfunction indicates a limitation in their use for the complete, long-term management of airway hyperresponsiveness.

Topics: Adrenal Cortex Hormones; Allergens; Animals; Bronchodilator Agents; Budesonide; Collagen; Disease Models, Animal; Female; Inflammation; Lung; Mice; Mice, Inbred BALB C; Respiratory Hypersensitivity; Time Factors; Treatment Outcome

This study evaluates whether the inhibitory effects of prednisolone phosphate (PLP) encapsulated in long-circulating liposomes (LCL-PLP) on tumor growth and tumor angiogenesis described previously can be generalized to other types of glucocorticoids (GC) encapsulated in LCL (LCL-GC). Four types of synthetic GC, i.e. budesonide disodium phosphate (BUP), dexamethasone disodium phosphate (DXP), methylprednisolone disodium phosphate (MPLP), and PLP, were selected based on the difference in their potency to activate the human glucocorticoid receptor. The effects of all LCL-GC on the production of angiogenic/inflammatory factors in vivo in the B16.F10 murine melanoma model as well as on the viability and proliferation of tumor cells and endothelial cells in vitro were investigated. Our results show that all four selected LCL-GC formulations inhibit tumor growth, albeit to different degrees. The differences in antitumor activity of LCL-GC correlate with their efficacy to suppress tumor angiogenesis and inflammation. The strongest antitumor effect is achieved by LCL-encapsulated BUP (LCL-BUP), due to the highest potency of BUP versus the other three GC types. The in vitro results presented herein suggest that LCL-BUP has strong cytotoxic effects on B16.F10 melanoma cells and the anti-proliferative effects of all LCL-GC towards angiogenic endothelial cells play a role in their antitumor activity.

Topics: Animals; Budesonide; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cells, Cultured; Colonic Neoplasms; Dexamethasone; Dose-Response Relationship, Drug; Drug Delivery Systems; Endothelium, Vascular; Glucocorticoids; Inflammation; Injections, Subcutaneous; Liposomes; Male; Melanoma, Experimental; Methylprednisolone; Mice; Mice, Inbred C57BL; Nanomedicine; Neovascularization, Pathologic; Prednisolone; Receptors, Glucocorticoid; Time Factors; Tumor Burden; Umbilical Veins

Clara cells are nonciliated secretory cells implicated in lung homeostasis by the synthesis of immunomodulatory and host defense products, being one of the most important the CC16 protein. In this study, we compared the effects of budesonide (BUD), an inhaled corticoid, on Clara cell biology and its ability to reverse morphofunctional changes induced in an allergic airway hyper-responsiveness mouse model. In normal mice, exposure to BUD induced morphological changes compatible with a state of maximal differentiation on CC16 positive cells which developed a prominent cupola filled up with numerous mitochondria rich in CYP2E1, a member of the cytochrome P450 family. Consequently, CYP2E1 expression raised significantly. Exposure to OVA provoked hypertrophy of Clara cells and an increment in their number per millimeter of basal membrane. These cells acquired a mucous cell phenotype characterized by a notorious expansion of the secretory granular content. Synthesis of CC16 was greatly up-regulated concurrent to the finding of MUC5AC expression and the increment of epidermal growth factor receptor (EGFR). Mitochondrial content decreased significantly with a consequent reduction in CYP2E1 expression. After BUD treatment of OVA-challenged animals, the majority of Clara cells regained their normal morphology and functional characteristics; CYP2E1 levels raised when compared to the OVA exposed group. The BUD potential to differentiate Clara cells appeared to be important for the regression of the profound changes generated by the allergic injury. These results demonstrated the wide range of stimuli that can modify different aspects of Clara cell biology, and highlighted the effects of budesonide as a modulator of P450 enzymes, which probably contributes to a complementary antiinflamatory activity.

Topics: Animals; Anti-Inflammatory Agents; Bronchi; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Cytochrome P-450 CYP2E1; Epithelial Cells; Glucocorticoids; Hypersensitivity; Inflammation; Mice; Up-Regulation; Uteroglobin

Chronic inflammation in asthma and chronic obstructive pulmonary disease drives pathological structural remodelling of the airways. Using tiotropium bromide, acetylcholine was recently identified as playing a major regulatory role in airway smooth muscle remodelling in a guinea pig model of ongoing allergic asthma. The aim of the present study was to investigate other aspects of airway remodelling and to compare the effectiveness of tiotropium to the glucocorticosteroid budesonide. Ovalbumin-sensitised guinea pigs were challenged for 12 weeks with aerosolised ovalbumin. The ovalbumin induced airway smooth muscle thickening, hypercontractility of tracheal smooth muscle, increased pulmonary contractile protein (smooth-muscle myosin) abundance, mucous gland hypertrophy, an increase in mucin 5 subtypes A and C (MUC5AC)-positive goblet cell numbers and eosinophilia. It was reported previously that treatment with tiotropium inhibits airway smooth muscle thickening and contractile protein expression, and prevents tracheal hypercontractility. This study demonstrates that tiotropium also fully prevented allergen-induced mucous gland hypertrophy, and partially reduced the increase in MUC5AC-positive goblet cell numbers and eosinophil infiltration. Treatment with budesonide also prevented airway smooth muscle thickening, contractile protein expression, tracheal hypercontractility and mucous gland hypertrophy, and partially reduced MUC5AC-positive goblet cell numbers and eosinophilia. This study demonstrates that tiotropium and budesonide are similarly effective in inhibiting several aspects of airway remodelling, providing further evidence that the beneficial effects of tiotropium bromide might exceed those of bronchodilation.

Topics: Adrenal Cortex Hormones; Allergens; Animals; Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Eosinophilia; Extracellular Matrix; Glucocorticoids; Guinea Pigs; Humans; Hypersensitivity; Inflammation; Male; Muscle, Smooth; Ovalbumin; Scopolamine Derivatives; Tiotropium Bromide; Trachea

Consumption of a naturally occurring polyphenol, resveratrol, in particular through drinking moderate amounts of red wine, has been suggested to be beneficial to health. A plethora of in vitro studies published demonstrate various anti-inflammatory actions of resveratrol. The aim of this research was to determine whether any of these anti-inflammatory effects translate in vivo in a rodent model of LPS induced airway inflammation. Resveratrol reduced lung tissue neutrophilia to a similar magnitude as that achieved by treatment with budesonide. This was associated with a reduction in pro-inflammatory cytokines and prostanoid levels. Interestingly, the reduction did not appear to be due to an impact on NF-kappaB activation or the expression of the respective genes as suggested by various in vitro publications. These results suggest that resveratrol may possess anti-inflammatory properties via a novel mechanism. Elucidation of this mechanism may lead to potential new therapies for the treatment of chronic inflammation.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Budesonide; Cytokines; Dinoprostone; DNA; Gene Expression; Inflammation; Inflammation Mediators; Lipopolysaccharides; Lung; Male; Neutrophils; NF-kappa B; Nitric Oxide Synthase Type II; Peritoneum; Peroxidase; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Resveratrol; Stilbenes; Wine

To investigate the effects of budesonide (BUD) used in an early phase or delayed phase on the airway inflammation and airway remodeling in ovalbumin (OVA) sensitized and challenged mice.. Forty mice were divided into 5 groups (8 in each group) including group A [ovalbumin (OVA) sensitized/challenged mice], group B (saline sensitized/challenged mice), group C (OVA sensitized/challenged mice treated by BUD in the early phase), group D (OVA-sensitized/challenged mice treated by BUD in the late phase) and group E (OVA-sensitized/challenged mice following saline challenge for 18 days). Mice were sensitized on days 0 and 14 by OVA and challenged from days 24 to 41 by OVA repeatedly to establish a murine model of asthma characterized by airway inflammation and airway remodeling. To assess the effects of BUD on the development of airway remodeling and on established airway remodeling, animals were treated with aerosolized BUD (0.5 mg/ml per day) from day 1 before OVA challenge (group C) and from day 18 following first OVA challenge (group D). The outcome measurements included airway inflammatory indices, eosinophils (EOS) count and amount of collagen deposition around the bronchus, area of airway smooth muscle, the degree of mucus secretion in the lumens and depth of airway smooth muscle (ASM) in different grade bronchus by HE, PAS and Masson's staining. The bronchoalveolar lavage fluids (BALF) were assayed for IL-5 and IFN-gamma levels.. In repeatedly OVA-challenged mice (group A), EOS counts in BALF increased significantly [(57.460 +/- 11.060) x 10(4)/ml] when compared with group B [(0.050 +/- 0.020) x 10(4)/ml, P < 0.01]. The IL-5 level increased significantly [(52.9 +/- 2.8) pg/ml vs (16.8 +/- 1.5) pg/ml, < 0.01] and IFN-gamma decreased significantly [(39.5 +/- 3.2) pg/ml vs (63.8 +/- 3.3) pg/ml, < 0.01]. Repeatedly OVA-challenged animals (group A) also developed an increase in EOS counts around bronchus [(1 018 +/- 118)/mm(2)] when compared with group B [(7 +/- 3)/mm(2), < 0.01], goblet cell hyperplasia [(46.0 +/- 5.8)% vs (1.8 +/- 0.5)%, < 0.01] and mucus hypersecretion [(score 2.98 +/- 0.23) vs (score 0.13 +/- 0.06), < 0.01], airway smooth muscle hypertrophy [(30.2 +/- 2.2)/microm(2)/microm vs (13.1 +/- 1.0) microm(2)/microm, < 0.01], enhanced collagen deposition of reticular basement membrane (RBM) [(24.9 +/- 1.3) microm(2)/microm vs (4.3 +/- 0.6) microm(2)/microm, all < 0.01]. Early treatment with BUD significantly reduced EOS counts in BALF [(7.140 +/- 1.250) x 10(4)/ml] as compared with group A [(57.460 +/- 11.060) x 10(4)/ml], < 0.01]. Early BUD treatment also significantly reduced EOS counts around bronchus [(214 +/- 26)/mm(2)], allergen-induced structural changes including goblet cell hyperplasia [(16.1 +/- 2.5)%] and mucus hypersecretion (1.10 +/- 0.15), airway smooth muscle hypertrophy [(14.0 +/- 0.7) microm(2)/microm], and RBM collagen deposition [(12.6 +/- 1.3) microm(2)/microm]. In group E, EOS counts in BALF [(1.250 +/- 0.330) x 10(4)/ml] were decreased significantly when compared with group A (< 0.01), but airway smooth muscle hypertrophy [(32.4 +/- 1.8) microm(2)/microm], and RBM collagen deposition [(22.8 +/- 1.7) microm(2)/microm] showed no reduction as compared with group A (all P > 0.05). Delayed BUD treatment significantly reduced EOS counts in BALF [(0.800 +/- 0.170) x 10(4)/ml], goblet cell hyperplasia [(29.3 +/- 4.3)%] and mucus hypersecretion (1.63 +/- 0.17, < 0.05 or < 0.01), but had no effects on OVA-induced airway smooth muscle hypertrophy [(30.1 +/- 1.8) microm(2)/microm] and RBM collagen deposition [(23.7 +/- 1.4) microm(2)/microm] as compared with group A (P > 0.05).. Early treatment with BUD inhibited the development of airway inflammation of airway remodeling. However, delayed use with BUD inhibited airway inflammation, but only partially reversed airway remodeling in a murine model of asthma.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Budesonide; Dose-Response Relationship, Drug; Inflammation; Leukocyte Count; Male; Mice; Mice, Inbred C57BL; Ovalbumin

Nuclear factor (NF)-kappaB is a transcription factor known to regulate the expression of many inflammatory genes, including cytokines, chemokines, and adhesion molecules. NF-kappaB is held inactive in the cytoplasm, bound to I-kappaB. The removal of I-kappaB, via the actions of inhibitor of kappaB (I-kappaB) kinase-2 (IKK-2), allows NF-kappaB to enter the nucleus.. To determine the impact of inhibiting IKK-2 on in vitro and in vivo models of airway inflammation.. The effect of inhibiting IKK-2 was assessed in stimulated, cultured, primary human airway smooth muscle cells and an antigen-driven rat model of lung inflammation.. The release of cytokines from cultured cells and inflammatory cytokine expression and cellular burden in the lung were determined.. Two structurally distinct molecules and dominant negative technology demonstrated that inhibition of IKK-2 activity completely blocked cytokine release from cultured cells, whereas the two glucocorticoid comparators had limited impact on granulocyte colony-stimulating factor, interleukin 8, and eotaxin release. In addition, in an in vivo antigen-driven model of airway inflammation, the IKK-2 inhibitor blocked NF-kappaB nuclear translocation, which was associated with a reduction in inflammatory cytokine gene and protein expression, airway eosinophilia, and late asthmatic reaction, similar in magnitude to that obtained with budesonide.. This study demonstrates that inhibiting IKK-2 results in a general reduction of the inflammatory response in vitro and in vivo. Compounds of this class could have therapeutic utility in the treatment of asthma and may, in certain respects, possess a beneficial efficacy profile compared with that of a steroid.

Topics: Amides; Animals; Anti-Inflammatory Agents; Asthma; Budesonide; Cells, Cultured; Chemokine CCL11; Chemokines, CC; Dexamethasone; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression; Granulocyte Colony-Stimulating Factor; Humans; I-kappa B Kinase; Inflammation; Interleukin-8; Muscle, Smooth; NF-kappa B; Rats; Respiratory System; Thiophenes

1. Stem cell factor (SCF) is a major growth factor for mast cells, promoting their differentiation and chemotaxis. Its expression is regulated by glucocorticoids in inflammatory conditions, showing an early increased protein expression, before the expected anti-inflammatory decrease (Da Silva et al., Br. J. Pharmacol. 2002:135,1634). 2. We here evaluated the early kinetic of SCF expression regulated by interleukin (IL)-1beta, budesonide and the combination of both in human lung fibroblasts in culture. 3. Budesonide potentiated the IL-1beta-enhanced expression of SCF mRNA (+103%) and protein (+98%) very shortly after treatment (at 30 min and 1 h, respectively). A gentle downregulation followed. This potentiating effect of budesonide was related to increased SCF mRNA stability and SCF gene transcription. 4. Deletion of a kappaB-like site that we identified in the first intron of the SCF gene, in a luciferase reporter system, abolished the potentiation by budesonide, as well as the effect of IL-1beta alone, as compared to the wild-type construction activity. 5. All budesonide-induced effects were glucocorticoid-receptor dependent, since they were reproduced by dexamethasone and blocked by RU486. 6. IL-1beta+budesonide did not affect the relative expression of the soluble and membrane-bound forms of SCF. 7. In conclusion, our results clearly show that glucocorticoids act very early to adversely increase the expression of SCF mRNA and protein in the inflammatory conditions created by IL-1beta, and that this effect involves increased mRNA stability and increased gene expression through activation of the NF-kappaB-like responsive element.

Topics: Budesonide; Cells, Cultured; DNA, Complementary; Down-Regulation; Drug Synergism; Fibroblasts; Glucocorticoids; Humans; Inflammation; Interleukin-1; Lung; Mifepristone; NF-kappa B; Plasmids; Receptors, Glucocorticoid; RNA Stability; RNA, Messenger; Stem Cell Factor; Tissue Engineering; Transcription, Genetic; Transfection

Evidence suggests that gender differences exist in the severity of many immunological diseases and their response to glucocorticosteroid treatment. In this report, we have used a murine model of ovalbumin-induced lung inflammation to address whether gender could affect the systemic response, airway inflammation and hyperreactivity and their responses to budesonide.. Following an acute ovalbumin challenge, actively sensitised BALB/c mice developed a time-dependent increase in interleukin-4 and interleukin-5 production and inflammatory cell influx into bronchoalveolar lavage fluid. Apart from an increased number of lymphocytes in female mice at day 3 post-challenge, none of the above parameters were affected by gender. Blood leukocyte numbers were also unaffected, whereas a two-fold increase in total serum immunoglobulin E was observed in female mice. Budesonide, given intranasally, did not affect the blood parameters, but dose-dependently inhibited the pulmonary inflammation and airway hyperreactivity in both male and female mice. Female mice were slightly less sensitive to budesonide's inhibitory action on interleukin-5 production and the development of airway hyperreactivity.. Our results suggest that, apart from a 2-fold increase in serum immunoglobulin E levels observed in female mice, gender is not a major factor in the present murine model of ovalbumin-induced lung inflammation. In contrast, gender might slightly influence the potency of test compounds such as steroids.

Topics: Allergens; Animals; Anti-Inflammatory Agents; Blood Cell Count; Bronchial Hyperreactivity; Bronchoalveolar Lavage; Budesonide; Disease Models, Animal; Female; Gender Identity; Immunoglobulin E; Inflammation; Male; Mice; Mice, Inbred BALB C

Cigarette smoke-triggered inflammation is considered to play a central role in the development of chronic obstructive pulmonary disease by a mechanism that may involve enhanced proinflammatory gene transcription. Histone acetylation and deacetylation is a key regulator of the specificity and duration of gene transcription. Disruption in the nuclear histone acetylation:deacetylation balance (chromatin remodeling) may result in excessive transcription of specific proinflammatory genes in the lungs. In this study we show that cigarette smoke exposure results in an influx of inflammatory cells and chromatin modifications in rat lungs. This was associated with an increase in the active phosphorylated form of p38 mitogen-activated protein kinase concomitant with increased histone 3 phospho-acetylation, histone 4 acetylation, and increased DNA binding of the redox-sensitive transcription factor nuclear factor-kappaB, independent of inhibitory protein-kappaB degradation, and activator protein 1. We also observed decreased histone deacetylase 2 activity, which is due to protein modification by aldehydes and nitric oxide products present in cigarette smoke. Furthermore, we show that corticosteroid treatment has no effect on smoke-induced proinflammatory mediator release. These findings suggest a possible molecular mechanism by which cigarette smoke drives proinflammatory gene transcription and an inflammatory response in the lungs.

Topics: Acetylation; Animals; Bronchoalveolar Lavage Fluid; Budesonide; Chemokine CCL4; Chemokine CXCL2; Chromatin Assembly and Disassembly; Cyclic AMP Response Element-Binding Protein; Cytokines; Histone Deacetylases; Histones; I-kappa B Proteins; Inflammation; Inflammation Mediators; Lung; Macrophage Inflammatory Proteins; Male; Monokines; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Smoking; Transcription Factor AP-1; Up-Regulation

1. Magnetic resonance imaging (MRI) was used to study noninvasively the effects of compounds to resolve inflammation induced by ovalbumin (OVA) challenge in the lungs of actively sensitised rats. 2. Marked oedematous signals were detected between 24 and 96 h following OVA in vehicle-treated animals. When administered 24 h after OVA, budesonide, a glucocorticosteroid, or 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171), a selective phosphodiesterase 4 inhibitor, increased the rate of resolution of established oedematous signals detected by MRI. The effect was evident 3 h after drug administration and the signals were nearly fully resolved at 96 h postchallenge. 3. The drug-induced rapid resolution of MRI signals was not accompanied by changes in parameters of inflammation in the bronchoalveolar lavage fluid, but was associated with perivascular oedema detected histologically. 4. In conclusion, the effects of anti-inflammatory drugs on a component of allergic inflammation can be monitored by following with MRI the rate of resolution of the associated oedematous signals.

Topics: Animals; Bronchoalveolar Lavage Fluid; Budesonide; Inflammation; Leukocytes; Lung; Magnetic Resonance Imaging; Male; Naphthyridines; Ovalbumin; Oxadiazoles; Peroxidase; Pulmonary Edema; Rats; Rats, Inbred BN; Respiratory Hypersensitivity

Asthma is a chronic inflammatory disease that is characterized by increased expression of multiple inflammatory genes. Chromatin modification plays a critical role in the regulation of these genes. Acetyaltion of histones by histone acetyltransferases (HATs) is associated with increased gene transcription, whereas hypocetylation induced by histone deacetylases (HDACs) is associated with suppression of gene expression. We have examined the expression and activity of HATs and HDACs in bronchial biopsies from normal subjects and subjects with asthma. There was no difference in the site of HDAC1-HDAC6 expression between normal subjects and subjects with asthma, but subjects with asthma had reduced HDAC enzymatic activity and reduced HDAC1 and HDAC2 protein expression, as measured by Western blotting. In contrast, subjects with asthma treated with inhaled steroids were found to have greater HDAC activity than untreated subjects with asthma, although still lower than control subjects. In contrast, although there was no change in the site of HAT (CREB binding protein and p300/CREB binding protein-associated factor) expression, HAT activity was increased in subjects with asthma. HAT activity was reduced to control levels in subjects with asthma treated with inhaled steroids. The increase in HAT activity and reduced HDAC activity in asthma may underlie the increased expression of multiple inflammatory genes, and this is reversed, at least in part, by treatment with inhaled steroids.

Topics: Administration, Inhalation; Adult; Anti-Inflammatory Agents; Asthma; Bronchoscopy; Budesonide; Female; Gene Expression; Histone Deacetylases; Humans; Inflammation; Male; Respiratory Function Tests; Respiratory System; Transcription, Genetic

Intratracheal instillation of Sephadex particles is a convenient model for assessing the impact of potential anti-inflammatory compounds on lung eosinophilia thought to be a key feature in asthma pathophysiology. However, the underlying cellular and molecular mechanisms involved are poorly understood. We have studied the time course of Sephadex-induced lung eosinophilia, changes in pulmonary T cell numbers, and gene and protein expression as well as the immunological and pharmacological modulation of these inflammatory indices in the Sprague Dawley rat. Sephadex increased T cell numbers (including CD4(+) T cells) and evoked a pulmonary eosinophilia that was associated with an increase in gene/protein expression of the Th2-type cytokines IL-4, IL-5, and IL-13 and eotaxin in lung tissue. Sephadex instillation also induced airway hyperreactivity to acetylcholine and bradykinin. A neutralizing Ab (R73) against the alphabeta-TCR caused 54% depletion of total (CD2(+)) pulmonary T cells accompanied by a significant inhibition of IL-4, IL-13 and eotaxin gene expression together with suppression (65% inhibition) of eosinophils in lung tissue 24 h after Sephadex treatment. Sephadex-induced eosinophilia and Th2 cytokine gene and/or protein expression were sensitive to cyclosporin A and budesonide, compounds that inhibit T cell function, suggesting a pivotal role for T cells in orchestrating Sephadex-induced inflammation in this model.

Topics: Acetylcholine; Animals; Antibodies, Monoclonal; Biomarkers; Bradykinin; Bronchial Hyperreactivity; Budesonide; Cell Movement; Cells, Cultured; Cyclosporine; Cytokines; Dextrans; Gene Expression Regulation; Inflammation; Interleukin-2; Intubation, Intratracheal; Lung; Lymphocyte Depletion; Male; Mast Cells; Pulmonary Eosinophilia; Rats; Rats, Sprague-Dawley; T-Lymphocyte Subsets; Time Factors

A detailed analysis has been carried out of the correlation between the signals detected by MRI in the rat lung after allergen or endotoxin challenge and parameters of inflammation determined in the broncho-alveolar lavage (BAL) fluid. MRI signals after allergen correlated highly significantly with the BAL fluid eosinophil number, eosinophil peroxidase activity and protein concentration. Similar highly significant correlations were seen when the anti-inflammatory glucocorticosteroid, budesonide, manifested against allergen. In contrast, following endotoxin challenge, mucus was the sole BAL fluid parameter that correlated significantly with the long lasting signal detected by MRI. Since edema is an integral component of pulmonary inflammation, MRI provides a noninvasive means of monitoring the course of the inflammatory response and should prove invaluable in profiling anti-inflammatory drugs in vivo. Further, the prospect of noninvasively detecting a sustained mucus hypersecretory phenotype in the lung brings an important new perspective to models of chronic obstructive pulmonary diseases.

Topics: Allergens; Animals; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Budesonide; Eosinophil Peroxidase; Inflammation; Lipopolysaccharides; Lung; Magnetic Resonance Imaging; Male; Mucus; Ovalbumin; Peroxidases; Pulmonary Disease, Chronic Obstructive; Pulmonary Edema; Pulmonary Eosinophilia; Rats; Rats, Inbred BN; Respiration

We examined the effects of different immunomodulators administered topically on asthmatic responses in a rat model of asthma. Sensitised Brown-Norway rats were administered rapamycin, SAR943 (32-deoxorapamycin), IMM125 (a hydroxyethyl derivative of D-serine(8)-cyclosporine), and budesonide by intratracheal instillation 1 h prior to allergen challenge. Allergen exposure induced bronchial hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid, and also an increase in eosinophils and CD2+, CD4+ and CD8+ T cells in the airways. Interleukin-2, interleukin-4, interleukin-5, interleukin-10, and interferon-gamma mRNA expression was upregulated by allergen exposure. Budesonide abolished airway inflammation, suppressed the mRNA expression for interleukin-2, interleukin-4, and interleukin-5 (P<0.03), and bronchial hyperresponsiveness (P<0.05). IMM125 suppressed airway infiltration of eosinophils, and CD8+ T cells (P<0.02), and prevented the upregulated mRNA expression for interleukin-4, interleukin-5, and interferon-gamma (P<0.02). Rapamycin suppressed CD8+ T cell infiltration in airway submucosa (P<0.03), and mRNA expression for interleukin-2 (p<0.002), while SAR943 suppressed interleukin-2, interleukin-4, and interferon-gamma mRNA (P<0.05). IMM125, rapamycin and SAR943 did not alter airway submucosal CD2+ and CD4+ T cell infiltration, and bronchial hyperresponsiveness. CD8+ T cells, in contrast to CD4+ T cells, are more susceptible to the inhibition by IMM125 and rapamycin, which also caused greater suppression of Th1 compared to Th2 cytokine mRNA expression. In this acute model of allergic inflammation, differential modulation of Th1 and Th2 cytokines may determine the effects of various immunomodulators on airway inflammation and bronchial hyperresponsiveness.

Topics: Acetylcholine; Administration, Topical; Animals; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Cyclosporins; Cytokines; Disease Models, Animal; Gene Expression Regulation; Immunosuppressive Agents; Inflammation; Male; Ovalbumin; Rats; Rats, Inbred BN; RNA, Messenger; Sirolimus; Specific Pathogen-Free Organisms; T-Lymphocytes; Vasodilator Agents

We have investigated the effect of 2(4-((2-carboxymethyl)phenyl)ethylamino)-5'-N-ethylcarboxamidoadenosine (CGS 21680), a potent and selective agonist at adenosine A2A receptors, on pulmonary inflammation induced by allergen challenge in the ovalbumin-sensitised, Brown Norway rat. Aerosol administration of ovalbumin (5 mg x ml(-1) for 60 min; calculated dose 0.4 mg x kg(-1)) induced increases in bronchoalveolar lavage fluid leukocyte numbers, protein content and myeloperoxidase and eosinophil peroxidase activities measured 24 h post challenge. CGS 21680 (10 and 100 microg x kg(-1) given intratracheally (i.t.) 30 min before and 3 h after allergen challenge) inhibited dose-dependently all the parameters of inflammation. Qualitatively similar results were obtained with the glucocorticosteroid, budesonide (0.1, 1 and 10 mg x kg(-1) given 3 h prior to ovalbumin challenge). CGS 21680 given i.t. reduced blood pressure in anaesthetised rats at similar doses to those at which anti-inflammatory effects were manifested. Both the anti-inflammatory and hypotensive responses to CGS 21680 were blocked by pretreatment with the selective adenosine A2A receptor antagonist, 4-(2-(7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a(1,3,5)triazin-5-yl amino)ethyl)phenol (ZM 241385), 3 mg x kg(-1) p.o., 1 h prior to the agonist. Thus, CGS 21680 manifests broad-spectrum anti-inflammatory activity in a model of allergic asthma in the Brown Norway rat through activation of adenosine A2A receptors. The striking similarity to budesonide, a clinically used anti-inflammatory agent, suggests that adenosine A2A receptor agonists may be useful alternatives to glucocorticosteroids in the treatment of asthma.

Topics: Adenosine; Allergens; Animals; Anti-Inflammatory Agents; Asthma; Blood Pressure; Budesonide; Dose-Response Relationship, Drug; Inflammation; Lung; Male; Ovalbumin; Phenethylamines; Purinergic P1 Receptor Agonists; Rats; Rats, Inbred BN; Receptor, Adenosine A2A; Triazines; Triazoles; Vascular Resistance

To determine the time to exacerbation and probability of a mild exacerbation of asthma, and the impact of eosinophilic inflammation on these parameters in patients with stable, well-controlled asthma.. A cohort of 31 patients with stable, well-controlled asthma receiving inhaled steroid treatment regularly were followed up for 1 year or until a mild exacerbation occurred. Mild exacerbation was defined as symptoms of asthma lasting > 48 h with a fall in peak expiratory flow > 20%. FEV(1), provocative concentration of methacholine causing a 20% fall in FEV(1), eosinophil count, and eosinophilic cationic protein (ECP) levels in blood and in sputum were measured at the first visit and every 2 months.. At baseline, the mean (SD) eosinophil count was 0.39 x 10(9)/L (0.21 x 10(9)/L) in blood and 13% (14%) in sputum; ECP was 30 microg/L (28 microg/L) in blood and 75 microg/L (85 microg/L) in sputum. Thirteen subjects experienced a mild exacerbation during the 1-year follow-up period. The mean time to mild exacerbation was 293 days (95% confidence interval [CI], 248 to 337 days), and the cumulative probability of not experiencing a mild exacerbation in 1 year was 49% (95% CI, 39 to 59%). An increased risk of mild exacerbation was associated with blood eosinophil count > 0.4 x 10(9)/L (relative risk 4.5; 95% CI of relative risk, 1.8 to 38.0), blood ECP > 20 microg/L (relative risk, 2.1; 95% CI of relative risk, 1.0 to 9.2), and sputum ECP > 40 microg/L (relative risk, 2.5; 95% CI of relative risk, 1.2 to 11.2), but was unassociated with other variables.. Patient with stable, well-controlled asthma are at risk of mild exacerbation during 1 year of follow-up despite regular inhaled steroid treatment. Eosinophilic inflammation expressed as eosinophil count and ECP is associated with higher risk of mild exacerbation.

Topics: Administration, Inhalation; Administration, Topical; Adolescent; Adrenergic beta-Agonists; Adult; Aged; Anti-Inflammatory Agents; Asthma; Blood Proteins; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Eosinophil Granule Proteins; Eosinophils; Follow-Up Studies; Forced Expiratory Volume; Glucocorticoids; Humans; Inflammation; Leukocyte Count; Longitudinal Studies; Methacholine Chloride; Middle Aged; Peak Expiratory Flow Rate; Ribonucleases; Risk Factors

Budesonide (BDS) is a potent corticosteroid that has important implications in the pharmacotherapy of inflammatory bowel disease, especially in the treatment of ulcerative colitis and Crohn's disease. BDS is available on the market in the form of enteric-coated preparations. However these products, similar to other available site-specific dosage forms, are not sufficiently selective to treat colonic inflammatory bowel disease. The objective of this study was to evaluate the efficacy of a new microparticulate system containing BDS, to treat experimentally induced colitis in rats. This microparticulate system consisted of BDS-containing hydrophobic cores, microencapsulated within an enteric polymer, which solubilizes at above pH 7, thus combining pH-sensitive and controlled-release properties. Colonic injury and inflammation were assessed by measuring colon/bodyweight ratio, myeloperoxidase (MPO) activity, and by scoring macroscopic and histological damage in colitic rats. Rats were treated orally with BDS, included in the developed system, once a day for 4 days after the induction of inflammation. A BDS suspension and BDS-containing enteric microparticles were included as control formulations in the experimental design. The administration of the new BDS delivery system significantly reduced the colon/bodyweight ratio compared with the administration of control formulations. Similarly, MPO activity and macroscopic and histological damage of the inflamed colonic segments decreased significantly when the BDS formulation was administered, compared with the results obtained after oral administration of the drug suspension. There were no significant differences, however, when the new treatment was compared with the control formulation consisting of simple enteric microparticles.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Body Weight; Budesonide; Colitis; Colon; Disease Models, Animal; Drug Compounding; Drug Delivery Systems; Inflammation; Male; Rats; Rats, Sprague-Dawley

Damage to the airway epithelium is one prominent feature of chronic asthma. Corticosteroids induce apoptosis in inflammatory cells, which in part explains their ability to suppress airway inflammation. However, corticosteroid therapy does not necessarily reverse epithelial damage. We hypothesized that corticosteroids may induce airway epithelial cell apoptosis as one potential explanation for persistent damage. We tested this hypothesis in cultured primary central airway epithelial cells and in the cell line 1HAEo(-). Treatment with dexamethasone, beclomethasone, budesonide, or triamcinolone each elicited a time-dependent and concentration-dependent cell death. This cell death was associated with cleavage of nuclear chromatin, mitochondrial depolarization, cytochrome c extrusion, activation of caspase-9, and expression of phosphatidylserine on the outer cell membrane. Inhibitors of caspase activity blocked apoptotic cell death, as did overexpression of the apoptosis regulators Bcl-2 or Bcl-x(L). We demonstrated that CD95 ligation is not essential for the corticosteroid-induced apoptosis in airway epithelial cells. These data demonstrate that corticosteroids induce apoptotic cell death of airway epithelium. This raises the possibility that at least one of the major components of chronic airway damage in asthma, epithelial shedding and denudation, may in part result from a major therapy for the disease.

Topics: Anti-Asthmatic Agents; Anti-Inflammatory Agents; Apoptosis; Asthma; bcl-X Protein; Beclomethasone; Bronchodilator Agents; Budesonide; Caspase 9; Caspases; Cells, Cultured; Chronic Disease; Cytochrome c Group; Dexamethasone; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; fas Receptor; Genes, bcl-2; Humans; Inflammation; Proto-Oncogene Proteins c-bcl-2; Receptors, Interleukin-2; Respiratory Mucosa; Time Factors; Triamcinolone

Spontaneous or steroid-induced eosinophil apoptosis occurring in vitro has not been demonstrated in lung tissues in vivo. This study examines cell apoptosis in rat lungs using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) technique and transmission electron microscopy (TEM). After establishing sustained lung edema and eosinophilia by challenge with Sephadex beads intratracheally, budesonide treatment was started intratracheally. Sephadex alone increased the total number of apoptotic cells, which were not efficiently engulfed by macrophages or other cells, in vivo. Yet apoptotic tissue eosinophils were exceedingly rare (1 of 360 TEM-analyzed eosinophils). By contrast, approximately 20% of eosinophils in the airway lumen were apoptotic, and unengulfed. Budesonide promptly inhibited edema but 3 d of steroid treatment were required to reduce the established tissue eosinophilia. Not at any time point did budesonide induce eosinophil apoptosis (0 of 318 TEM-analyzed tissue eosinophils). We conclude that (1) eosinophil apoptosis can occur but is a rare event in vivo in respiratory tract tissues; (2) airway tissue eosinophils, rather than undergoing apoptosis, are eliminated by migration into airway lumen followed by apoptosis and mucociliary clearance; (3) anti-inflammatory steroid treatment may not increase eosinophil apoptosis in vivo nor may it affect the luminal entry of eosinophils; (4) steroids permit elimination of eosinophils into airway lumen and slowly resolve established lung eosinophilia.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Bronchoalveolar Lavage Fluid; Budesonide; Dextrans; Disease Models, Animal; Drug Evaluation, Preclinical; In Situ Nick-End Labeling; Inflammation; Leukocyte Count; Male; Microscopy, Electron, Scanning Transmission; Mucociliary Clearance; Pulmonary Edema; Pulmonary Eosinophilia; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Representative glucocorticosteroids (GCS) and phosphodiesterase IV (PDE4) inhibitors were compared in several models of pulmonary inflammation ranging in severity. Lung tissue eosinophil peroxidase (EPO) levels rather than bronchoalveolar lavage fluid (BALF) EPO or eosinophil percentages were used to indicate eosinophil recruitment after intratracheal instillation of sephadex beads in rats or nebulized ovalbumin in sensitized guinea pigs. A single oral or intratracheal administration of a GCS was effective against mild and robust sephadex-induced eosinophilia whereas the PDE4 inhibitors evaluated appeared more effective in the milder sephadex models. The GCS were also more effective against sephadex-induced than ovalbumin-induced eosinophilia. The effectiveness of the GCS and PDE4 inhibitors improved when the severity of the ovalbumin-induced eosinophilia was decreased. Multiple day dosing also improved activity. These studies indicated that activity was influenced greatly by administration protocols, the severity of the inflammatory response and possibly the method used for estimating eosinophil recruitment.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Androstadienes; Animals; Asthma; Beclomethasone; Benzamides; Budesonide; Cyclic Nucleotide Phosphodiesterases, Type 4; Dexamethasone; Dextrans; Disease Models, Animal; Enzyme Inhibitors; Eosinophil Peroxidase; Eosinophils; Fluticasone; Glucocorticoids; Guinea Pigs; Inflammation; Lung; Male; Ovalbumin; Peroxidases; Pyridines; Rats; Rats, Sprague-Dawley; Rolipram

Topics: Administration, Inhalation; Asthma; Bronchodilator Agents; Budesonide; Eosinophils; Glucocorticoids; Humans; Inflammation; Lung Diseases, Obstructive; Sputum

To improve our understanding of the inflammatory mechanisms underlying severe disease, a biopsy study was performed comparing 15 clinically unstable glucocorticoid-dependent asthmatics, 10 mild asthmatics, and 10 control subjects. Compared with mild asthma, severe asthma was characterized by reduced mucosal eosinophilia. Whilst no significant differences were found in the numbers of mast cells, neutrophils, CD3+ and CD4+ T-cells between the three groups, up to a 4-fold increase In the numbers of activated T-lymphocytes bearing the interleukin (IL)-2 receptor (IL-2R) was found in the mucosa in severe asthma compared to mild asthma (p = 0.03) and control subjects (p = 0.003). Compared to control subjects, the mucosa of severe asthmatics contained significantly (p = 0.02) higher numbers of IL-5+ cells, with no differences between mild and severe disease. In contrast, staining for the anti-IL-4 monoclonal antibody 3H4 revealed that biopsies from mild asthmatics contained more IL4+ cells than biopsies from severe asthmatics and control subjects (p = 0.0008). In the severe asthmatics, a close correlation (r(s) = 0.76, p = 0.005) was found between the numbers of IL-2R-bearing cells and the variability in peak expiratory flow. In conclusion, persistent T-cell activation is a prominent feature of severe asthma. These results also indicate that interleukin-5, and not interleukin-4, is upregulated in severe disease.

Topics: Administration, Topical; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Asthma; Bronchi; Budesonide; CD4-Positive T-Lymphocytes; Cell Count; Eosinophils; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Immunoglobulin E; Inflammation; Interleukin-4; Interleukin-5; Lymphocyte Activation; Male; Mast Cells; Middle Aged; Mucous Membrane; Peak Expiratory Flow Rate; Prednisolone; Receptors, Interleukin-2; T-Lymphocytes

The relationship between nitric oxide in exhaled air, levels of sputum eosinophils, sputum eosinophil cationic protein (ECP) and urinary eosinophil protein X (EPX) excretion has not yet been investigated in corticosteroid-dependent childhood asthma. Therefore, taking 25 children with stable asthma (mean age 11.2 yrs) treated with inhaled corticosteroids and nine nonatopic healthy control children (mean age 12.8 yrs) the level of exhaled NO was measured by means of a chemiluminescence analyser before and after sputum induction. This was conducted as a slow vital capacity manoeuvre under standardized conditions with a target flow of 70 mL x s(-1) against a resistance of 100 cm H2O x L(-1) x s. Sputum induction was performed by inhalation of hypertonic saline (3, 4, and 5%) in a standardized manner and a single sample of urine was collected. Exhaled NO (p = 0.01), absolute eosinophil cell counts in sputum (p = 0.02), sputum ECP (p = 0.09) and urinary EPX excretion (p = 0.02) were higher in asthmatics compared to control children. Exhaled NO was positively correlated with sputum ECP (r(s) = 0.59, p = 0.002), urinary EPX (r(s) = 0.42, p = 0.03), and sputum eosinophils (r(s) = 0.30, p = 0.15) in the asthmatic children. These correlations appeared to be pronounced after sputum induction, where NO values had decreased (p = 0.01). None of the correlations were observed in the group of nonatopic control subjects. Additionally there were significant correlations between sputum ECP and sputum eosinophils (r(s) = 0.69, p<0.001) as well as between sputum ECP and urinary EPX excretion (r(s) = 0.58, p = 0.003) in the asthmatics. Exhaled NO provides information about the degree of eosinophilic airway inflammation and thus appears to be a useful and easy-to-perform inflammatory marker in corticosteroid-dependent asthma.

Topics: Administration, Inhalation; Administration, Topical; Adolescent; Anti-Inflammatory Agents; Asthma; Blood Proteins; Breath Tests; Bronchi; Budesonide; Child; Eosinophil Granule Proteins; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Glucocorticoids; Humans; Inflammation; Inflammation Mediators; Leukocyte Count; Male; Nitric Oxide; Ribonucleases; Sputum; Vital Capacity

11beta-hydroxysteroid dehydrogenase (11betaHSD) reversibly converts hydrocortisone, the predominant active endogenous glucocorticoid in humans, to its inactive metabolite cortisone by oxidizing the 11-hydroxy group to an 11-keto group. Because this enzyme is highly expressed in human bronchial epithelial cells, we hypothesized that it regulates epithelial responses to glucocorticoids by reducing levels of hydrocortisone available to bind to the glucocorticoid receptor. Primary human bronchial epithelial cells (PBECs) were isolated from seven autopsy specimens and cultured in F12/Dulbecco's modified Eagle's medium with 5% fetal bovine serum until approximately 80% confluent. Cells were preincubated with 10(-9) M to 10(-5) M hydrocortisone for 24 h in the presence or absence of 10(-6) M of the 11betaHSD inhibitor glycyrrhetinic acid, after which the cells were stimulated with 5 ng/ml interleukin-1beta for 24 h. Granulocyte macrophage colony-stimulating factor (GM-CSF) levels were quantitated in the resulting supernatants by enzyme-linked immunosorbent assay. Hydrocortisone inhibited GM-CSF release in stimulated PBEC with a concentration that produces 50% inhibition of maximum effect (IC(1/2)max) of 5.0 x 10(-8) M. In the presence of glycyrrhetinic acid, the potency of hydrocortisone was increased approximately 33-fold (IC(1/2)max with glycyrrhetinic acid, 1.5 x 10(-9) M). Hydrocortisone activity was maximally enhanced at concentrations between 10(-9) M and 10(-8) M, levels that are comparable to plasma levels of hydrocortisone not bound to plasma proteins. Glycyrrhetinic acid had no effect on the suppression of GM-CSF release by hydrocortisone in the transformed cell line BEAS-2B, which does not express the 11betaHSD enzyme. Glycyrrhetinic acid also had no effect on the inhibition of GM-CSF release in PBECs by the synthetic glucocorticoids budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide, steroids not metabolized by 11betaHSD. Together, these findings suggest that metabolism of hydrocortisone by 11betaHSD may regulate glucocorticoid activity in human airway epithelial cells.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Bronchi; Budesonide; Cells, Cultured; Dose-Response Relationship, Drug; Epithelial Cells; Glycyrrhetinic Acid; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hydrocortisone; Hydroxysteroid Dehydrogenases; Inflammation; Lung

The aim of this pilot study was to determine the effect of early inhaled budesonide on clinical and inflammatory parameters in preterm infants ventilated for respiratory distress syndrome.. Neither the inflammatory process associated with respiratory distress syndrome nor the progression to bronchopulmonary dysplasia appeared to be altered by treatment with inhaled budesonide.

Topics: Bronchodilator Agents; Bronchopulmonary Dysplasia; Budesonide; Humans; Infant, Newborn; Infant, Premature; Inflammation; Longitudinal Studies; Respiratory Distress Syndrome, Newborn; Treatment Failure

Inflammation of the intestine causes pain and altered motility, at least in part through effects on the enteric nervous system. While these changes may be reversed with healing, permanent damage may contribute to inflammatory bowel disease (IBD) and post-enteritis irritable bowel syndrome. Since little information exists, we induced colitis in male Sprague-Dawley rats with dinitrobenzene sulfonic acid and used immunocytochemistry to examine the number and distribution of enteric neurons at times up to 35 days later. Inflammation caused significant neuronal loss in the inflamed region by 24 hours, with only 49% of neurons remaining by days 4 to 6 and thereafter, when inflammation had subsided. Eosinophils were found within the myenteric plexus at only at the earliest time points, despite a general infiltration of neutrophils into the muscle wall. While the number of myenteric ganglia remained constant, there was significant decrease in the number of ganglia in the submucosal plexus. Despite reduced neuronal number and hyperplasia of smooth muscle, the density of axons among the smooth muscle cells remained unchanged during and after inflammation. Intracolonic application of the topical steroid budesonide caused a dose-dependent prevention of neuronal loss, suggesting that evaluation of anti-inflammatory therapy in inflammatory bowel disease should include quantitative assessment of neural components.

Topics: Animals; Anti-Inflammatory Agents; Axons; Benzenesulfonates; Budesonide; Cell Count; Colitis; Colon; Dose-Response Relationship, Drug; Enteric Nervous System; Immunohistochemistry; Inflammation; Male; Myenteric Plexus; Neurons; Peroxidase; Rats; Rats, Sprague-Dawley; Submucous Plexus; Thiolester Hydrolases; Time Factors; Ubiquitin Thiolesterase

The inflammatory cell infiltrate in bronchial biopsies of 12 aspirin-sensitive asthmatic (ASA) subjects and eight non-aspirin-sensitive (non-ASA) control subjects have been compared. Biopsies were taken from a right middle or lower lobe segmental carina using fiberoptic bronchoscopy. The biopsies were snap-frozen in OCT, and sections 5 microns thick were doubled immunostained using a rabbit polyclonal antibody to the enzyme 5-lipoxygenase (5-LO) and with a monoclonal antibody to neutrophils (NP57), macrophages (EMB11), and total (BMK13) and activated eosinophils (EG2), mast cells (AA1), and T-lymphocytes (anti-CD3). There was no significant difference in the total numbers of cells staining for 5-LO between the two groups of subjects. As a percentage of total 5-LO cells, there were significantly more mast cells (12.9 +/- 3.8% versus 3.4 +/- 3.1%; p = 0.039) and total eosinophils (34.7 +/- 9.4% versus 11.1 +/- 3.8%; p = 0.044) and significantly fewer macrophages (23.3 +/- 6.1% versus 39.8% +/- 5.3; p = 0.041) in the bronchial biopsies from ASA subjects as compared with non-ASA patients. The numbers of neutrophils, T-lymphocytes, and activated eosinophils were similar for the two groups. The increased numbers of eosinophils and mast cells identified in the bronchial tissue from aspirin-sensitive asthmatic subjects may be the source of the enhanced cysteinyl leukotriene production observed in these subjects.

Topics: Administration, Inhalation; Administration, Oral; Administration, Topical; Adrenal Cortex Hormones; Adult; Animals; Anti-Inflammatory Agents; Aspirin; Asthma; Biopsy; Bronchi; Bronchodilator Agents; Bronchoscopy; Budesonide; Cell Count; Coloring Agents; Data Interpretation, Statistical; Drug Hypersensitivity; Eosinophils; Female; Glucocorticoids; Humans; Immunohistochemistry; Inflammation; Macrophages; Male; Middle Aged; Neutrophils; Prednisolone; Pregnenediones; Rabbits; T-Lymphocytes

Recognition of the therapeutic value of glucocorticosteroids in the treatment of inflammation has preceded awareness of the mechanism(s) of action of these drugs. We recently showed that coculture of human T84 epithelial monolayers for 2 days with anti-CD3 activated peripheral blood mononuclear cells (A-PBM) led to impaired ion transport responses and reduced barrier function. We tested the hypothesis that budesonide, as a member of the new generation of more topically selective steroids, could prevent these immune-mediated epithelial abnormalities. Budesonide added to the coculture system dose-dependently inhibited the following functional T84 abnormalities measured in Ussing chambers: reduced transport responses (decreased short-circuit current changes to carbachol (raises [Ca2+]i) and forskolin (raises cAMP, cyclic adenosine monophosphate(i)); and increased permeability (decreased resistance and increased fluxes of 3H-mannitol and 51CrEDTA). For the beneficial effects of budesonide to be observed, PBM pretreatment (> or = 3 hr) and daily addition (for 2 days) to the coculture system was necessary. Budesonide (10(-7) M) dramatically reduced A-PBM proliferation (measured by 3H-thymidine incorporation) and cytokine (IL-1beta, IL-2, IL-6, IFN-gamma, TNF-alpha) production, but was not cytotoxic to immune cells. Budesonide treatment of T84 epithelial cells alone did not directly affect epithelial physiology, nor did it prevent epithelial abnormalities evoked by subsequent exposure to A-PBM or conditioned media from immune cells. Our studies showed that budesonide prevents epithelial dysfunction in this model by inhibiting activation of both T cells and monocytes.

Topics: Adult; Anti-Inflammatory Agents; Budesonide; Cells, Cultured; Epithelium; Female; Humans; Inflammation; Male; Middle Aged; Monocytes; Pregnenediones; T-Lymphocytes

Recent studies from our laboratory have identified a network of constitutively class II major histocompatibility complex (MHC) (Ia)-bearing dendritic cells (DC) within the epithelium of the conducting airways of laboratory animal species and in humans. These studies have also demonstrated that the density of the DC network increases within the airway epithelium in response to inflammatory challenge. In the present report, we demonstrate that exposure of adult rats to inhaled steroids leads to a rapid but readily reversible decrease both in the number of airway intraepithelial DC, and in their surface Ia expression. Similar changes are also seen in response to high doses of systemic dexamethasone. In addition, we demonstrate that steroid inhalation reduces the rate of postnatal expansion of the airway intraepithelial DC network in rat pups, and prevents the rapid expansion of the DC network in adults which occurs during the acute inflammatory response following inhalation of microbial stimuli.

Topics: Administration, Topical; Androstadienes; Animals; Anti-Inflammatory Agents; Beclomethasone; Budesonide; Dendritic Cells; Epithelium; Female; Fluticasone; Glucocorticoids; Inflammation; Pregnenediones; Rats; Rats, Inbred Strains; Trachea

Airway inflammation is implicated in the pathogenesis of the airway hyperresponsiveness in asthma. An increased production of inflammatory cell progenitors may contribute to asthmatic airway inflammation. Although the number of circulating inflammatory cell progenitors in asthmatic subjects increases after allergen inhalation, no direct evidence exists for increased bone marrow progenitor production. We examined the effect of allergen inhalation on bone marrow progenitor production in seven dogs that develop allergen-induced airway hyperresponsiveness. The effect of inhaled budesonide, a corticosteroid known to be effective in the treatment of asthma, on allergen-induced bone marrow progenitor production and airway hyperresponsiveness was also examined. Allergen inhalation increased airway responsiveness (P < 0.001) and the number of granulocyte-macrophage colony-forming units (CFU) when cultured with dog serum and either recombinant canine stem cell factor (rcSCF) (P < 0.001) or granulocyte colony-stimulating factor (rcG-CSF) (P = 0.035). Budesonide treatment reduced the allergen-induced increases in airway responsiveness (P = 0.005) and abolished the allergen-induced increases in the numbers of CFU cultured with dog serum and either rcSCF (P < 0.001) or rcG-CSF (P = 0.009). These findings provide the first direct evidence that allergen inhalation increases bone marrow progenitor production and suggest that such increases may contribute to the development of airway hyperresponsiveness in asthma. In addition, the effectiveness of inhaled corticosteroids in asthma may result, in part, from their ability to suppress bone marrow production of inflammatory cells.

Topics: Administration, Inhalation; Allergens; Animals; Ascaris suum; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Disease Models, Animal; Dogs; Hematopoietic Stem Cells; Inflammation; Pregnenediones; Respiratory Function Tests

Intratracheal instillation of Sephadex beads induced a long-lasting inflammation in the rat lung as seen by an increase in lung weights. Repeated instillation enhanced this reaction and increased lung endothelin-1 content 3.5 times. Budesonide given s.c. abolished these effects and even reduced basal endothelin-1 content by 72%. The tissue content of the sensory neuropeptide neurokinin A were unaffected by both treatments. Endothelin has been proposed to play a part in the pathogenesis of bronchial asthma. If it is so, the ability of budesonide to reduce endothelin-1 content could thus be added to the list of beneficial effects of glucocorticosteroids in these conditions.

Topics: Administration, Inhalation; Animals; Budesonide; Dextrans; Endothelins; Female; Inflammation; Lung; Male; Neurokinin A; Organ Size; Pregnenediones; Rats; Rats, Sprague-Dawley

Repeated airway exposures to toluene diisocyanate (TDI) may cause sensitization and asthma. This study has examined the acute inflammatory response to TDI in guinea-pig tracheobronchial airways, the development of increased sensitivity to TDI and the effects of xanthines and a glucocorticoid on these responses to TDI. A restricted surface area of the tracheobronchial mucosa of Ketalar-Xylazin anaesthetized guinea-pigs was exposed to TDI, dissolved in olive oil, by means of 1 min infusions through an oral catheter. The TDI-induced inflammatory process was quantified by determination of airway luminal entry of plasma. Already 3 nl (approximately 20 pmol) of TDI produced a significant and sustained exudation response (P less than 0.001 to P less than 0.01, 5 and 17 hr after exposure). Pretreatment with intravenous enprofylline (25 mumol/kg) intraperitoneally or 26 mumol/kg by tracheal superfusion) was without effect. Two repeated exposures to TDI 3 nl (on days 1 and 8) made the animals hyperresponsive to TDI so that on day 15 a previously subthreshold dose of TDI (0.3 nl) produced significant exudation both at 5 and 17 hr after exposure (P less than 0.001 to P less than 0.01). Similarly, two repeated dermal exposures to a large dose of TDI (20 microliters) lowered the threshold for tracheal provocation with TDI. Budesonide (2.6 mumol/kg orally) given daily during the topical airway 'sensitization' regimen (days 1-14) significantly reduced the response to the subsequent 0.3 nl challenge dose of TDI (P less than 0.05). The effects of daily treatments with either theophylline (100 mumol/kg) or enprofylline (50 mumol/kg) were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Cutaneous; Administration, Topical; Animals; Budesonide; Guinea Pigs; Inflammation; Intubation, Intratracheal; Male; Pregnenediones; Respiratory Hypersensitivity; Theophylline; Toluene 2,4-Diisocyanate; Xanthines

The effect of corticosteroid on an acute inflammation in the lungs was studied in guinea pigs exposed to an aerosol of bacterial endotoxin, the subsequent inflammatory response was evaluated counting the number of cells obtained from airway lavage and in the lung interstitium as well as the chemotactic effect of alveolar macrophages. Pretreatment with corticosteroid decreased the number of neutrophils in the airways at 24 hours after exposure but did not influence neutrophils in airways or lung interstitium at 4 hours after exposure, not the secretion of chemotactic factor(s) from alveolar macrophages at that time. It is suggested that the antiinflammatory effect of corticosteroids is a protective effect on the epithelium, preventing the late influx of serum fluid and neutrophils into the airways.

Topics: Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Budesonide; Chemotaxis, Leukocyte; Eosinophils; Escherichia coli; Female; Guinea Pigs; Inflammation; Lipopolysaccharides; Lung Diseases; Lymphocytes; Macrophages; Male; Neutrophils; Pregnenediones

Topics: Adrenergic beta-Agonists; Aerosols; Airway Obstruction; Aspirin; Asthma; Bronchi; Bronchodilator Agents; Budesonide; Calcium Channel Blockers; Cromolyn Sodium; Drug Administration Schedule; Epinephrine; Glucocorticoids; Gold; Humans; Inflammation; Mucous Membrane; Osteoporosis; Parasympatholytics; Patient Education as Topic; Prednisone; Pregnenediones; Theophylline

The very potent topical anti-inflammatory glucocorticosteroids (GCS) most widely used are either 17 alpha-esters of halogenated 16-methyl-17 alpha-hydroxycorticosteroids (e.g. beclomethasone 17 alpha, 21-dipropionate = BDP) or 16 alpha, 17 alpha-acetals of halogenated 16 alpha, 17 alpha-dihydroxy corticosteroids (e.g. triamcinolone acetonide = TA). The purpose of the present investigation was to increase the ratio between the topical anti-inflammatory (TAIP) and the systemic potencies (SP) of GCS 16 alpha, 17 alpha-acetals, as such compounds are not biotransformed in the lung. Structure-activity investigations in rodents showed that fluoro substituents in positions 6 alpha or 9 alpha or both 6 alpha, 9 alpha 9 alpha increased SP more than TAIP. On the other hand, nonsymmetrical 16 alpha, 17 alpha-acetal substitution increased TAIP more than SP. The best TAIP:SP ratio was obtained with budesonide, which contains this new type of acetal substituent, but has no halogen atoms in the steroid nucleus. In the rat and the mouse budesonide has a 5--10 times better TAIP:SP ratio than 16 alpha, 17 alpha-acetonides, like TA, as well as 17 alpha-ester GCS, like BDP. The improved ratio for budesonide is probably due to a high intrinsic GCS activity at the site of application combined with an effective inactivation by biotransformation after systemic absorption. The importance of the inactivation in the liver was verified by experiments in which the biotransformation capacity of the liver was blocked by SKF-525 A.

Topics: Animals; Asthma; Beclomethasone; Budesonide; Glucocorticoids; Humans; Inflammation; Male; Mice; Mice, Inbred Strains; Pregnenediones; Rats; Rats, Inbred Strains

Topical anti-inflammatory ('intracutaneous vasoconstriction') and systemic glucocorticoid potencies (depression of plasma cortisol) were compared in human volunteers after administration of the glucocorticoids budesonide, beclomethasone dipropionate (BDP) and prednisolone. After topical application budesonide was about twice as potent as BDP and more than 1 000 times more potent than prednisolone and hydrocortisone in inducing 'vasoconstriction'. After oral administration, on the other hand, budesonide was one half to one third as potent as BDP in depressing plasma cortisol. After inhalation budesonide was only half as potent as BDP. When inhaled budesonide was compared to oral prednisolone budesonide 1 600 micrograms and prednisolone 5 mg were shown to have the same effect on plasma cortisol. The improved ratio between the topical and the systemic glucocorticoid effect of budesonide, makes the drug a promising alternative for aerosol treatment in asthma.

Topics: Adult; Beclomethasone; Budesonide; Dose-Response Relationship, Drug; Humans; Inflammation; Middle Aged; Prednisolone; Pregnenediones