Barrier function of airway tract epithelium

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

Tight junctions are composed of several transmembrane proteins (including occludin, multiple claudins, junctional adhesion molecule (JAM)) and cytoplasmic scaffolding proteins containing PDZ-domains (zonula occludens ZO-1, ZO-2, ZO-3), cingulin, and MUPP1. Transmembrane proteins in the junction connect the membranes of adjacent cells to make a tight seal, while scaffolding proteins anchor transmembrane proteins to the cytoskeleton. Claudins function to regulate the paracellular permeability in airway epithelium, whereas occludin has been shown to regulate de novo assembly of tight junctions. 107 Although JAM association with tight junctions is well studied, its function at tight junctions remains unclear. In recent years, the coxsackievirus and adenovirus receptor (CAR), which serves as a receptor for viruses, was also shown to be a transmembrane protein located in the tight junction and interacts with ZO-1 in airway epithelial cells. 108 Further, CAR expression was shown to be required for formation of functional tight junctions and limits permeability of macromolecules. Airway epithelial cells isolated from healthy smokers and patients with COPD show reduced expression of occludin and claudins, which may contribute to the observed barrier dysfunction in these subjects. 90 Several respiratory viruses have been shown to increase permeability and decrease transepithelial resistance of airway epithelium by either interacting with tight junction proteins or by dissociating adherens junction complexes. Coxsackievirus and adenovirus bind to CAR, inducing disassembly of the tight junction and reduction in transepithelial resistance (TER). 109, 110 Previously, we demonstrated that rhinovirus (RV) dissociates ZO-1, occludin, and claudin 4 from the tight junctions and increases bacterial association and translocation across polarized airway epithelium. 93, 111, 112 also been shown to decrease the expression defensin genes in the airways. 135 Herr et al. showed that hBD2 is significantly reduced in the pharyngeal wash and sputum of current or former smokers compared with non-smokers, and exposure of airway epithelium to cigarette smoke in vitro inhibited induction of HBD2 by bacteria. 148 Cathelicidins are another class of antimicrobial peptides and LL37 is the only human cathelicidin identified to date. LL37 binds to lipopolysaccharides and inactivates its biological function. Overexpression of human LL37 in cystic fibrosis mouse models increased killing of P. aeruginosa and reduced the ability of this bacterium to colonize the airways. 149 Airway epithelial cells also generate oxidants such as nitric oxide (NO) and hydrogen peroxide. Three NO synthases contribute to production of NO in airway epithelia: the constitutively expressed NOS1 and NOS3, and inducible NOS2. Viral infections and pro-inflammatory cytokines induce expression of NOS2 and defective NOS2 expression is responsible for increased viral replication in cystic fibrosis, while overexpression of NOS2 provides protection against viral infection. 150, 151 Recently we demonstrated that COPD airway epithelial cells show a trend in decreased expression of NOS2 and this was associated with impaired clearance of rhinovirus. 123 Extracellular hydrogen peroxide is produced by dual oxidase 1 and 2. These belong to a family of NADPH oxidases and are located in the plasma membrane and secrete hydrogen peroxide to the extracellular milieu. The dual oxidase-generated hydrogen peroxide in combinat