The pathology of small airways disease in COPD: historical aspects and future directions

Abstract

Small airways disease (SAD) is a cardinal feature of chronic obstructive pulmonary disease (COPD) first recognized in the nineteenth century. The diverse histopathological features associated with SAD underpin the heterogeneous nature of COPD. Our understanding of the key molecular mechanisms which drive the pathological changes are not complete. In this article we will provide a historical overview of key histopathological studies which have helped shape our understanding of SAD and discuss the hallmark features of airway remodelling, mucous plugging and inflammation. We focus on the relationship between SAD and emphysema, SAD in the early stages of COPD, and the mechanisms which cause SAD progression, including bacterial colonization and exacerbations. We discuss the need to specifically target SAD to attenuate the progression of COPD.

Intermittent exposure to whole cigarette smoke alters the differentiation of primary small airway epithelial cells in the air-liquid interface culture

“…COPD is a disease that strongly affects the small airways 17,39 . To investigate the underlying pathophysiological and molecular mechanisms in vitro, a new protocol for SAEC ALI cultures and novel methods for their analysis were established.…”

Extracellular matrix remodelling in COPD

“…Chronic inflammation in COPD is associated with increased numbers of fibroblasts in the airways, as well as inflammatory cells such as macrophages, neutrophils, CD4+ and CD8+ T-lymphocytes [70]. These cells secrete MMPs, such as MMP-1, MMP-8, MMP-13 and MMP-12, that degrade ECM molecules and result in the destruction and remodelling of the ECM in small airways [71] and in the parenchyma (figure 1b) [72].…”

Loss of C/EBPα in Chronic Cigarette Smoke Exposure: A SAD Day for Chronic Obstructive Pulmonary Disease

“…Tobacco or cigarette smoke (CS) exposure is a main driver of chronic obstructive pulmonary disease (COPD), a progressive disease involving small airway disease (SAD) with airway remodeling and fibrosis, and loss of alveoli and terminal bronchioles (1,2). Human studies have identified pathology of small airways ,2 mm of diameter as the major contributor to increased airflow resistance in COPD (1).…”

“…In addition, CS exposure is associated with development of centrilobular emphysema (CLE). CLE is distinct from panlobular and paraseptal emphysema (PSE), the latter being more common in alpha-1 antitrypsin deficiency (2). Emphysema pathology is defined by irreversible enlargement of the peripheral airspaces distal to the terminal bronchioles (3,4).…”

“…Lung destruction and pathogenesis of COPD and emphysema can be driven by disrupted balance in the levels of proteinases and antiproteinases, most clearly demonstrated by alpha-1 antitrypsin deficiency, which is responsible for protection from neutrophilderived serine proteases, such as neutrophil elastase (10,11). Although recent reviews have highlighted the role of inflammation-induced protease activity in eliciting extracellular matrix destruction (1,2), the cellular and molecular mechanisms regulating the development of protease/antiprotease imbalance during SAD is not fully understood.…”