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).

Keywords: COPD; airway epithelium; basal cells; lung cancer; smoking.

Figure 1.

Basal cells and the airway epithelium in the normal human nonsmoker. (A) Schematic of the normal human airway epithelium. Basal cells represent 34% of the cell population in the trachea, decreasing generally to 10% in the small airways. Ciliated, secretory, and undifferentiated intermediate cells represent the other cell types. Tight junctions connecting the differentiated ciliated and secretory cells contribute to the integrity of the epithelial barrier. All of the epithelial cells are attached to the basement membrane. (B and C) Basal cells in the normal nonsmoker. (B) Human large airway epithelium. The basal cells are cuboidal, KRT5⁺ cells lining the basement membrane. Hematoxylin and eosin; bar = 50 μm. (C) Transmission electron microscopy of a basal cell purified from the normal human airway epithelium. Bar = 2 μm. (D) Normal differentiation of the airway epithelium. The basal cell population contains stem/progenitor cells, which can self-renew and generate differentiated airway epithelium. During normal turnover and repair, the basal cells proliferate and differentiate, generating undifferentiated intermediate cells, which further differentiate into ciliated cells under the control of FOXJ1 and other transcriptional regulators shown and to secretory cells under the control of the Notch pathway. Generation of mucus-producing cells is governed by transcription factors SPDEF and FOXA3.

Figure 2.

Isolation of basal cells from human the airway epithelium. (A) Basal cells are obtained from the airway epithelium using fiberoptic bronchoscopy and brushing (42). The purified basal cells were cytokeratin 5, p63, and CD151 positive but were negative for mesenchymal (N-cadherin), secretory (MUC5AC), or ciliated (β-tubulin) lineages. Bar = 10 μm. (B) Progenitor function of basal cells. The purified basal cells differentiate to ciliated and secretory lineages when placed in air–liquid interface cultures. Shown is evidence of the ciliated lineage (β-tubulin IV positive). Bar = 10 μm.

Figure 3.

Abnormalities of the biology, function, and differentiation of the airway epithelium with cigarette smoking and the development of chronic obstructive pulmonary disease. The initial changes are in disordered biology, with a distorted transcriptome and regression to a more primitive state under the influence of inherited and acquired genetics. This evolves into disordered function and differentiation, with stem/progenitor cell fatigue, distorted differentiation, and, in some cases, malignant transformation. The first histologic abnormality associated with smoking is basal cell hyperplasia, followed by loss of ciliated cells, shorter cilia, mucus cell hyperplasia, loss of cell junctions, and squamous metaplasia.