Airway Basal Cells. The “Smoking Gun” of Chronic Obstructive Pulmonary Disease

Abstract

The earliest abnormality in the lung associated with smoking is hyperplasia of airway basal cells, the stem/progenitor cells of the ciliated and secretory cells that are central to pulmonary host defense. Using cell biology and 'omics technologies to assess basal cells isolated from bronchoscopic brushings of nonsmokers, smokers, and smokers with chronic obstructive pulmonary disease (COPD), compelling evidence has been provided in support of the concept that airway basal cells are central to the pathogenesis of smoking-associated lung diseases. When confronted by the chronic stress of smoking, airway basal cells become disorderly, regress to a more primitive state, behave as dictated by their inheritance, are susceptible to acquired changes in their genome, lose the capacity to regenerate the epithelium, are responsible for the major changes in the airway that characterize COPD, and, with persistent stress, can undergo malignant transformation. Together, these observations led to the conclusion that accelerated loss of lung function in susceptible individuals begins with disordered airway basal cell biology (i.e., that airway basal cells are the "smoking gun" of COPD, a potential target for the development of therapies to prevent smoking-related lung disorders).

Reduced Expiratory Flow Rate among Heavy Smokers Increases Lung Cancer Risk. Results from the National Lung Screening Trial–American College of Radiology Imaging Network Cohort

“…Why smokers with underlying airflow obstruction are at greater risk of lung cancer than smokers with normal lung function remains unknown (13)(14)(15)(16). Early hypotheses suggested that patients with COPD have a greater accumulation of carcinogens in the airway (1,2).…”

“…Other hypotheses link lung cancer with underlying emphysema and lung remodeling (13,14). The innate immune response has been implicated in both COPD and lung cancer in large prospective studies (15)(16)(17)(18). Systemic inflammation, reflecting innate immune hyperresponsiveness, has been linked to both progression of lung remodeling leading to COPD and DNA damage leading to lung cancer (18).…”

Club cells and CC16: another “smoking gun”? (With potential bullets against COPD)

“…Club cells, identified during the 19th century, are one of these targets and thorough efforts have aimed at identifying them as another "smoking gun" candidate [3]. CC16, a 15.8-kDa protein, is secreted by these nonciliated bronchiolar cells and is supposed to have anti-inflammatory properties.…”

Regenerative potential of human airway stem cells in lung epithelial engineering

“…Smoking-associated lung diseases, such as COPD, pose an unique challenge. The basal cell population isolated from COPD patients has been reported to display an altered gene expression profile and diminished capacity for regeneration (48). While the regenerative capacity is reduced in basal cells from smokers (43), it is not a completely lost, suggesting that a regenerative subpopulation remains.…”