Barrier function of airway tract epithelium

Ganesan, Shyamala; Comstock, Adam T; Sajjan, Uma S

Tight and adherens junctions located at the apicolateral border of airway epithelial cells also contribute significantly to the barrier function of conductive airway tract epithelium. Like in other mucosal epithelium, paracellular permeability of airway epithelium is maintained through the cooperation of two mutually exclusive structural components: tight junctions and adherens junctions on the apicolateral membranes. 33 While tight junctions regulate the transport of solutes and ions across epithelia, adherens junctions mediate cell to cell adhesion and promote formation of tight junctions. [84] [85] [86] In normal airway epithelium, these intercellular junctions prevent inhaled pathogens and other environmental insults from injuring the airways, and also serve as signaling platforms that regulate gene expression, cell proliferation, and differentiation. 87, 88 Therefore, disassociation or sustained insults that affect junctional complexes will disrupt not only barrier function, but may also interfere with normal repair and differentiation of airway epithelium. Airway epithelium is leaky, hyperproliferative, and abnormally differentiated in smokers and in patients with asthma and COPD compared with airway epithelium in healthy smokers. [89] [90] [91] [92] Infection with viruses or have all been shown to stimulate hypersecretion of mucus. [44] [45] [46] [47] [48] [49] Therapies targeted to limit exaggerated mucus hypersecretion in addition to modulating mucociliary clearance in chronic airways disease may prevent airways obstruction. The rate of mucociliary clearance depends on the composition of the airway surface liquid (ASL) lining the airway surface. ASL is made up of two layers, an upper viscoelastic layer of mucins secreted by the goblet cells and submucosal glands, 50 which floats on a lower periciliary layer containing large membrane-bound glyocproteins, as well as tethered mucins (muc-1, muc-4 and muc-16). 51, 52 The periciliary layer is relatively less viscous, approximately 7 μM in height which corresponds to a length of outstretched cilia and acts as a lubricating layer for cilia to beat. 32, 52, 53 Hydration of ASL is regulated by coordinated activity of Chloride secretion (Cl − ) and Sodium (Na + ) absorption channels. The combination of Cl − secretion and reduced reabsorption of Na + favors normal ASL hydration and efficient mucociliary clearance. In normal airways, the coordinated functioning of ATP-activated cystic fibrosis transmembrane conductance regulator (CFTR), calcium-activated Cl − channel (CaCC), outwardly rectifying Cl − channel (ORCC), Cl − channel 2 (CLC2), and epithelial Na + channel (ENaC) regulate the ASL hydration. 54 CFTR negatively regulates ENac and therefore absent or dsyfunctional CFTR increases ENaC activity leading to hyperabsorption of Na + , an increased driving force for fluid reabsorption resulting in reduced ASL depth and impaired mucociliary clearance as observed in the chronic airway disease cystic fibrosis. 54 In cystic fibrosis patients this condition is further exacerbated by excessive mucus production due to goblet cell metaplasia and hyperplasia, and submucosal gland hypertrophy resulting in obstruction of airways.