Airway Epithelial Repair, Regeneration, and Remodeling after Injury in Chronic Obstructive Pulmonary Disease

Abstract

In chronic obstructive pulmonary disease (COPD), exacerbations are generally associated with several causes, including pollutants, viruses, bacteria that are responsible for an excess of inflammatory mediators, and proinflammatory cytokines released by activated epithelial and inflammatory cells. The normal response of the airway surface epithelium to injury includes a succession of cellular events, varying from the loss of the surface epithelium integrity to partial shedding of the epithelium or even complete denudation of the basement membrane. The epithelium then has to repair and regenerate to restore its functions, through several mechanisms, including basal cell spreading and migration, followed by proliferation and differentiation of epithelial cells. In COPD, the remodeling of the airway epithelium, such as squamous metaplasia and mucous hyperplasia that occur during injury, may considerably disturb the innate immune functions of the airway epithelium. In vitro and in vivo models of airway epithelial wound repair and regeneration allow the study of the spatiotemporal modulation of cellular and molecular interaction factors-namely, the proinflammatory cytokines, the matrix metalloproteinases and their inhibitors, and the intercellular adhesion molecules. These factors may be markedly altered during exacerbation periods of COPD and their dysregulation may induce remodeling of the airway mucosa and a leakiness of the airway surface epithelium. More knowledge of the mechanisms involved in airway epithelium regeneration may pave the way to cytoprotective and regenerative therapeutics, allowing the reconstitution of a functional, well-differentiated airway epithelium in COPD.

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…Unfortunately, few studies to date have attempted to address this possibility and no knockout mice for DUOX1/2 are yet available. Analysis of bronchial biopsies from smokers or patients with COPD revealed decreased expression of DUOX1 and ~2-fold upregulation of DUOX2 (207,208), which might be related to characteristic epithelial alterations within these subjects, such as goblet cell hyperplasia and squamous metaplasia (115,209). Analysis of bronchial tissues from patients with severe cystic fibrosis indicated decreased DUOX2 expression (210), thus suppressing a component of host defense leading to enhanced respiratory infections in these subjects.…”

“…1), which are critically involved in cell growth and differentiation and morphogenesis (13,38,52,110,111). Because the airway epithelium is continuously subjected to injury due to environmental stress, it possesses an exceptional capacity to repair itself (112,113), through a coordinated response involving rapid spreading and migration of neighboring cells, cell proliferation and redifferentiation, to restore the original mucociliary epithelium (103,114,115). Using in vitro wound models in cultured airway epithelial systems, DUOX1 was found to play a critical role in cell migration as part of the wound repair response (87,108), illustrating an additional function of DUOX1 in maintenance of epithelial integrity.…”

Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

“…In humans, the SAE consists of four major cell types: ciliated, secretory, columnar and basal cells (30,33). These cells provide a barrier and innate immunity that protect the airway from environmental stressors, pollutants and pathogens (34)(35)(36). Cigarette smoking is associated with disordering of the differentiation of the SAE basal cells, with consequent disordered function of the airway mucociliary barrier (34,35).…”

“…Cigarette smoking is associated with disordering of the differentiation of the SAE basal cells, with consequent disordered function of the airway mucociliary barrier (34,35). The ability of the SAE to alter gene expression in response to external stimuli is critical to airway defense and repair mechanisms (30,31,34,36).…”

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

“…However, recently, airway wall thickening has been identified as a major independent predictor of the severity of physiologic airway obstruction in COPD patients stratified by the criteria established by the Global Initiative for Obstructive Lung Disease (GOLD; http://www.goldcopd.com/), suggesting that airway-wall fibrosis contributes to airway obstruction (5). COPD is caused by the noxious effects of tobacco smoke, which leads to airway epithelial injury and the induction of changes such as squamous metaplasia (SM), the reversible replacement of the normal columnar epithelium by squamous epithelium (6). In 1978, Cosio et al noted that SM correlated with the severity of airway obstruction, suggesting that SM and airway obstruction may be linked (7).…”