pulmicort and Emphysema

A placebo-controlled, double blind, cross-over study of inhaled budesonide was carried out to examine its effectiveness in the treatment of chronic airflow limitation (CAL). Fourteen patients (11 males, mean age 66 years) with stable CAL received placebo treatment for four weeks followed by inhaled budesonide 400 micrograms BD for eight weeks. Response was assessed by measuring forced expiratory volume in one second (FEV1). There was no significant improvement in the overall spirometric measurements and symptom scores except a reduction in daily peak expiratory flow rate fluctuation (p < 0.05). However, individual patients showed significant increase in FEV1. Two patients (14%) had greater than 30% increase in FEV1 in response to inhaled corticosteroids. This response could not be predicted from history of allergy, skin test, bronchial challenge test, peripheral blood or sputum eosinophilia. We conclude that only a minority of patients with stable CAL may respond to inhaled budesonide. Nonetheless, patients who are symptomatic despite treatment with maximum doses of bronchodilators may have a trial of inhaled corticosteroids in order to demonstrate any additional benefit.

Topics: Administration, Inhalation; Administration, Topical; Aerosols; Aged; Anti-Inflammatory Agents; Bronchial Provocation Tests; Bronchitis; Bronchodilator Agents; Budesonide; Chronic Disease; Double-Blind Method; Emphysema; Glucocorticoids; Humans; Male; Middle Aged; Pregnenediones; Respiratory Mechanics

Chronic obstructive pulmonary disease (COPD) is a health problem that results in death, commonly due to the development of pulmonary hypertension (PH). Here, by utilizing a mouse model of intratracheal elastase-induced emphysema that presents three different phases of COPD, we sought to observe whether budesonide/glycopyrronium/formoterol fumarate (BGF) triple therapy could prevent COPD-PH in addition to ameliorating COPD progression.. We utilized intratracheal elastase-induced emphysema mouse model and performed experiments in three phases illustrating COPD progression: inflammatory (1 day post-elastase), emphysema (3 weeks post-elastase) and PH (4 weeks post-elastase), while treatments of BGF and controls (vehicle, one-drug, and two-drug combinations) were started in prior to elastase instillation (inflammatory phase), at day 7 (emphysema), or at day 14 (PH phase). Phenotype analyses were performed in each phase. In vitro, A549 cells or isolated mouse lung endothelial cells (MLEC) were treated with TNFα with/without BGF treatment to analyze NFκB signaling and cytokine expression changes.. We observed significant reductions in the proinflammatory phenotype observed in the lungs and bronchoalveolar lavage fluid (BALF) 1 day after elastase administration in mice treated with BGF compared with that in mice administered elastase alone (BALF neutrophil percentage, p = 0.0011 for PBS/Vehicle vs. PBS/Elastase, p = 0.0161 for PBS/Elastase vs. BGF). In contrast, only BGF treatment significantly ameliorated the elastase-induced emphysematous lung structure and desaturation after three weeks of elastase instillation (mean linear intercept, p = 0.0156 for PBS/Vehicle vs. PBS/Elastase, p = 0.0274 for PBS/Elastase vs. BGF). Furthermore, BGF treatment prevented COPD-PH development, as shown by improvements in the hemodynamic and histological phenotypes four weeks after elastase treatment (right ventricular systolic pressure, p = 0.0062 for PBS/Vehicle vs. PBS/Elastase, p = 0.027 for PBS/Elastase vs. BGF). Molecularly, BGF acts by inhibiting NFκB-p65 phosphorylation and subsequently decreasing the mRNA expression of proinflammatory cytokines in both alveolar epithelial and pulmonary endothelial cells.. Our results collectively showed that BGF treatment could prevent PH in addition to ameliorating COPD progression via the inhibition of inflammatory NFκB signaling.

Topics: Animals; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Emphysema; Endothelial Cells; Formoterol Fumarate; Fumarates; Glycopyrrolate; Hypertension, Pulmonary; Mice; NF-kappa B; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema

Phosphoinositide 3-kinase (PI3K) plays an important role in tissue inflammatory reactions and fibrotic processes. The objective of this study was to evaluate the potential mechanism and therapeutic effects of PI3K inhibitor on pancreatic elastase (PE)-induced acute and chronic lung inflammation, edema, and injury.. Rats were terminated at 7 or 28 days after an intratracheal challenge with PE and intranasal instillation with a PI3K inhibitor, SHBM1009. Alterations of airway epithelial cells and myofibroblasts were studied in vitro.. Lung inflammation, edema, and injury; emphysema; and tissue remodeling were measured after PE instillation with or without treatment with PI3K inhibitor and budesonide. Cellular biologic functions were monitored.. SHBM1009 could prevent PE-induced acute lung inflammation, edema, and injury, and chronic lung inflammation, remodeling, and emphysema. Different patterns of inhibitory effects of SHBM1009 and BEZ235, a dual PI3K/mechanistic target of rapamycin inhibitor, on PE-challenged epithelial cells were observed. PE per se reduced epithelial cell proliferation and stability through the inhibition of cell division rather than promoting cell death, in dose- and time-dependent patterns. Effects of PI3K inhibitors on cells were associated with the severity of PE challenges.. PI3K plays a critical role in the development of acute and chronic lung injury, including the process of tissue remodeling and emphysema. PI3K inhibitors could be new therapeutic alternatives for chronic lung diseases.

Topics: Acute Disease; Airway Remodeling; Animals; Anti-Inflammatory Agents; Budesonide; Cell Proliferation; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Emphysema; Enzyme Inhibitors; Imidazoles; Male; Pancreatic Elastase; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pneumonia; Quinolines; Rats; Rats, Wistar; Time Factors

Emphysema is one component of chronic obstructive pulmonary disease (COPD), a respiratory disease currently increasing in prevalence worldwide. The mainstay therapy adopted to treat patients with COPD is glucocorticoids; unfortunately, this treatment has limited impact on disease symptoms or underlying airway inflammation.. There is an urgent need to develop therapies that modify both the underlying inflammation, thought to be involved in disease progression, and the structural changes in the emphysematous lung.. We have characterized an elastase-driven model of experimental emphysema in the rat that demonstrates COPD-like airway inflammation and determined the impact of a clinically relevant glucocorticoid.. We observed an increase in lung neutrophils, lymphomononuclear cells, mucus production, and inflammatory cytokines. Also present were increases in average air space area, which are associated with emphysema-like changes in lung function, such as increased residual volume and decreased flow; these increases in area were maintained for up to 10 weeks. In addition, we observed that elastase-induced airway neutrophilia is steroid resistant. Interestingly, the inflammation observed after elastase administration was found to be temporally associated with a lack of nuclear factor-kappaB pathway activation. This apparent nuclear factor-kappaB-independent inflammation may explain why treatment with a glucocorticoid was ineffective in this preclinical model and could suggest parallels in the steroid-resistant human disease.. We believe that this model, in addition to its suitability for testing therapies that may modify existing emphysema, could be useful in the search for new therapies to reduce the steroid-resistant airway inflammation evident in COPD.

Topics: Algorithms; Animals; Anti-Inflammatory Agents; Budesonide; Disease Models, Animal; Disease Progression; Drug Resistance; Emphysema; Male; NF-kappa B; Pancreatic Elastase; Pneumonia; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Signal Transduction