The role of airway remodeling in the pathogenesis and treatment of chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is currently considered the third leading cause of death in the world. COPD represents an important public health challenge and a socio-economical problem that is preventable and treatable. The main cause of COPD is chronic inhalation of cigarette smoke, and other harmful constituents of air pollution, which cause epithelial injury, chronic inflammation and airway remodeling. Airway remodeling is most prominent in small airways. It is due to infiltration of the airways by inflammatory cells, such as neutrophils, eosinophils, macrophages, and immune cells, including CD8+ T-cells, Th1, Th17 lymphocytes, and innate lymphoid cells group 3. Fibroblasts, myofibroblasts, and airway smooth muscle (ASM) cells also contribute to airway remodeling by depositing extracellular matrix (ECM) proteins, which increase the thickness of the airway wall. Activated inflammatory cells, and structural cells secrete cytokines, chemokines, growth factors, and enzymes which propagate airway remodeling. Airway remodeling is an active process which leads to thickness of the reticular basement membrane, subepithelial fibrosis, peribronchiolar fibrosis, and ASM cells hyperplasia and hypertrophy. It is also accompanied by submucosal glands and goblet cells hypertrophy and mucus hypersecretion, and angiogenesis. Epithelial mesenchymal transmission (EMT) plays a key role in airway remodeling. In patients with COPD and smokers, cellular reprograming in epithelial cells leads to EMT, whereby epithelial cells assume a mesencymal phenotype. Additionally, COPD is associated with increased parasympathetic cholinergic activity, which leads to ASM cells hypercontractility, increased mucus secretion, and vasodilatation. Treatment of COPD is intricate because of the heterogeneous nature of the disease, which requires specific treatment of the pathophysiological pathways, such as airway inflammation, ASM cell hypercontractility, and parasympathetic cholinergic hyperreactivity. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 strategy report recommends personalized approach for the treatment of COPD. However, some patients with COPD are unresponsive to the standards of care. They may require a triple combination of LABA/LAMA/ICS. Single-inhaler triple therapy (SITT), such as fluticasone fuorate/vilanterol/umeclidinium has been shown to significantly improve symptoms and asthma control, reduce moderate and severe exacerbations, and to improve lung function.