Chronic obstructive pulmonary disease (COPD) is currently considered the third leading cause of death in the world, and its prevalence, especially the milder form, is estimated to be about 25% of adults above 40 years. The main cause of COPD is chronic inhalation of cigarette smoke, and other indoor and outdoor harmful constituents of air pollution.
Airway remodeling is a common feature of asthma but it also occurs in patients with chronic obstructive pulmonary disease. It involves mostly peripheral airways, and to a lesser extent larger airways causing thickening of the airway wall, and narrowing of the bronchial lumen. The airway structural changes lead to progressive and irreversible decline in pulmonary function.
Airway remodeling is an active process involving deposition of extracellular matrix (ECM) proteins by fibroblasts, myofibroblasts, and airway smooth muscle (ASM) cells, subepithelial fibrosis, peribronchial fibrosis, and ASM cells hyperplasia and hypertrophy. Airway remodeling is also accompanied by submucosal gland and goblet cell hypertrophy and mucus hypersecretion, angiogenesis, and parasympathetic nerve dysfunction. Peribronchial fibrosis, play an important role in stiffening the bronchiolar walls, increasing airflow resistance, and in progressive decline in pulmonary function. Inflammatory cells and immune cells, such as neutrophils, eosinophils, CD68+ macrophages, mast cells, CD8+ T cells, Th1, Th17 lymphocytes, and innate lymphoid cells group 3, play a key role in airway remodeling. They secrete by inflammatory cytokines, chemokines, growth factors, adhesion molecules, and enzymes which orchestrates the remodeling process. Metalloproteinases (MMPs), especially MMP-9 secreted by neutrophils and macrophages play an important role in the remodeling process in patients with COPD and asthma. Integrins also play an important role in airway hyperresponsiveness, remodeling, they act synergistically with VEGF to promote angiogenesis.
Several chemokines, cytokines, growth factors secreted by activated inflammatory and immune, and structural cells are involved in the airway remodeling process. They include chemokines, namely RANTES and eotaxins; cytokines, including interleukin-1β (IL-1β), IL-6, IL-8, IL-22, and TNF-α; and growth factors, such as TGFβ, FGF, EGFR, and IGF.
Treatment of severe COPD is difficult because of the complexity and heterogeneity of the pathogenesis of the irreversible airflow obstruction due to remodeling. The maintenance treatment of COPD should target all the components of airway remodeling, such as ASM cell hypercontractility, parasympathetic dysfunction, and airway inflammation. The Food and Drug Administration (FDA) has approved single-inhaler triple therapy (SITT) for maintenance treatment of patients with COPD. Long-acting β2 agonists (LABA), long-acting muscarinic receptor antagonists (LAMA), and inhaled corticosteroids (ICS) have potent synergistic and favourable pharmacological interaction, and additive bronchodilator effect. Single-inhaler triple therapy may have anti-remodeling activities in addition to bronchodilatation and anti-inflammatory activity.
Breztri Aerosphere is a single-inhaler, fixed-dose, triple combination of budesonide, an inhaled corticosteroid, with formoterol fumarate a long-acting beta2-agonist, and glycopyrrolate, a long-acting muscarinic antagonist, delivered in a pressurized metered-dose inhaler. Triple fixed-dose inhaler therapy has been shown to significantly reduce moderate or severe exacerbations by 24% compared with dual combination metered-dose inhaler consisting of glycopyrronium and formoterol fumarate (P < .001), and a reduction of 13% compared with PT009 (budesonide and formoterol fumarate) (P = .003). Triple combination inhalers have also been found to significantly improve lung function. They are convenient for the patients, and possible improve compliance. 24% lower rate of COPD exacerbations compared with glycopyrronium/formoterol fumarate (P < .001) and a 13% reduction compared with PT009 (budesonide/formoterol fumarate) (P = .003) which showed a significant reduction in moderate or severe COPD exacerbations compared with dual-combination therapy, according to the release. Healio previously reported results of ETHOS, a phase 3, randomized, double-blind, multicenter, parallel-group trial that examined the safety and efficacy of triple therapy. Patients were randomly assigned to receive twice-daily inhaled triple combination therapy (320 µg or 160 µg budesonide, 18 µg glycopyrrolate and 9.6 µg formoterol) or one of two dual-combination therapies ( 18 µg glycopyrrolate plus 9.6 µg formoterol or 320 µg budesonide plus 9.6 formoterol). Results showed that the triple-therapy group had a 24% lower rate of COPD exacerbations compared with glycopyrronium/formoterol fumarate (P < .001) and a 13% reduction compared with PT009 (budesonide/formoterol fumarate) (P = .003).