The airway epithelium establishes a boundary between the internal and the external environment that protects against potential injury and infection caused by inhaled particles, debris and microbial pathogens. In order to maintain the health of the lungs and surrounding tissues, the epithelium utilizes numerous defense mechanisms that complement the barrier function of the epithelium. These include the expression of a broad array of innate immune receptors including Toll-like, NOD-like and RIG-I receptors which facilitate the expression and secretion of multiple defense molecules, cytokines and chemokines essential for recruitment and activation of immune cells. Chronic inflammation of the airways due to prolonged or repeated exposure to noxious agents can result in epithelial remodeling and fibrosis that leaves the airways more susceptible to infection due to disruption of innate immune processes. Loss of epithelial integrity compromises normal mucosal defense, underscoring the important relationship between structure and function of the airway epithelium. The pseudostratified airway epithelium is composed of multiple cell types. Multipotent, progenitor basal cells are transit-amplifying cells that reside along the basal lamina of the airway which differentiate into surface cells. Basal cells are instrumental in the maintenance of normal epithelial structure and function as well as driving orderly regeneration after injury. Differentiated surface cells can be divided into two distinct lineages: secretory and ciliated. Secretory cells synthesize and secrete gel-forming polymeric mucins that absorb water to form mucus. Ciliated cells propel the mucus gel towards the pharynx and out of the lungs by the directional, synchronized beating of cilia on the cell surface, effectively removing entrapped particles and pathogens from the lungs by a process known as mucociliary clearance. Current treatment strategies for patients with asthma, COPD and other inflammatory airway disorders emphasize a combined therapy involving inhaled corticosteroid (ICS) and long-acting β2-agonists (LABA) aimed at reducing inflammation and increasing airway caliber. LABAs, such as Salmeterol and Formoterol, are effective long-acting inhaled bronchodilators. These drugs stimulate increases in cAMP which activates protein kinase A (PKA) dependent signaling pathways in airway smooth muscle, leading to relaxation and a decrease in airway resistance. The therapeutic benefit of ICS treatment is attributed to transrepression of specific genes induced by proinflammatory transcription factors such as NF-kB and AP-1, limiting airway hyperresponsiveness. Other effects of corticosteroids on airway epithelial cells suggest a role in surface cell diversity by increasing the number of ciliated epithelial cells and decreasing mucus hypersecretion, therefore promoting mucociliary clearance. Although effective at reducing inflammatory immune reactions and airway hyperresponsiveness, the effects of combined therapy on the airway epithelium are not as well characterized. Therefore, the overall goal of the present thesis was to investigate the role of glucocorticoids in the development of the ion transport phenotype of bronchial epithelial cells during differentiation. We hypothesized that hydrocortisone (HC) is necessary for in vitro differentiation of airway basal cells into a pseudostratified epithelium with ciliated and secretory surface cells. Additionally, we hypothesized a role for HC in the development of normal transepithelial ion-transport pathways, both transcellular and paracellular, that are essential for mucociliary clearance. The results of the present studies demonstrate that early glucocorticoid exposure affects the development and maintenance of specific ion-transport pathways required for mucociliary clearance. These findings indicate that ICS treatment supports mucosal defense through direct interactions with the airway epithelium.
University of Minnesota Ph.D. dissertation. September 2016. Major: Integrative Biology and Physiology. Advisor: Scott O'Grady. 1 computer file (PDF); ix, 148 pages.
The Role of Hydrocortisone on the Development and Maintenance of Ion Transport Pathways Essential to Mucociliary Clearance in Differentiated Normal Human Bronchial Epithelial Cells.
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