Pathogenesis of COPD (Persistence of Airway Inflammation): Why Does Airway Inflammation Persist After Cessation of Smoking?

The structural features of airways in patients with COPD are airway wall inflammation, fibrosis, muscle hypertrophy, and goblet cell metaplasia. These structural cellular changes contribute to mucus hypersecretion and destruction of the alveolar walls and a decline in forced expiratory volume in one second (FEV(1)). At the cellular level, macrophages, T lymphocytes, and neutrophils, driven by cytokines including interleukin-8 (IL-8), gather on the airways. The main cause of COPD inflammation is cigarette smoke. Smoke causes an increase in the secretion of matrix metalloproteinase (MMPs) and neutrophilic elastase from epithelial cells and neutrophils, which are responsible for mucin production and destruction of the lung. Initially, cigarette smoke influences the expression of pattern recognition receptors (PRRs) including Toll-like receptors (TLRs), the intracellularly located nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and receptors for advanced glycation end products (RAGE) on lung epithelial cells, endothelial cells, and leukocytes in the lung. These actions bring about the production of cytokines and activation of inflammatory cells, leading to production of MMPs and neutrophilic elastase. The inflammatory changes persist for several months and years after smoking cessation and are sometimes irreversible. Damage-associated molecular patterns (DAMPs) released from dying cells after cigarette smoking increase the number of apoptotic cells, suppress efferocytosis, induce hypoxia and oxidative stress, and prolong the inflammatory changes, even after smoking cessation. Viral and bacterial infections of the respiratory tract then fortify these inflammatory responses. Exacerbations of COPD then worsen the deterioration of COPD.