Pulmonary epithelial barrier function: some new players and mechanisms

Abstract

The pulmonary epithelium serves as a barrier to prevent access of the inspired luminal contents to the subepithelium. In addition, the epithelium dictates the initial responses of the lung to both infectious and noninfectious stimuli. One mechanism by which the epithelium does this is by coordinating transport of diffusible molecules across the epithelial barrier, both through the cell and between cells. In this review, we will discuss a few emerging paradigms of permeability changes through altered ion transport and paracellular regulation by which the epithelium gates its response to potentially detrimental luminal stimuli. This review is a summary of talks presented during a symposium in Experimental Biology geared toward novel and less recognized methods of epithelial barrier regulation. First, we will discuss mechanisms of dynamic regulation of cell-cell contacts in the context of repetitive exposure to inhaled infectious and noninfectious insults. In the second section, we will briefly discuss mechanisms of transcellular ion homeostasis specifically focused on the role of claudins and paracellular ion-channel regulation in chronic barrier dysfunction. In the next section, we will address transcellular ion transport and highlight the role of Trek-1 in epithelial responses to lung injury. In the final section, we will outline the role of epithelial growth receptor in barrier regulation in baseline, acute lung injury, and airway disease. We will then end with a summary of mechanisms of epithelial control as well as discuss emerging paradigms of the epithelium role in shifting between a structural element that maintains tight cell-cell adhesion to a cell that initiates and participates in immune responses.

Keywords: epithelial barrier; ions; lung; permeability; transport.

Fig. 1.

The epidermal growth factor receptor (EGFR) is restricted to the basal surface of the airway epithelial cells. This figure serves to highlight how the integrity of the apicoadherens junction can regulate epithelial cell signaling. Under conditions of low paracellular permeability created by the cytoskeleton and cell-cell contacts, there is segregation of EGF ligand and receptor, thereby inhibiting constant cellular signaling. In conditions of increased paracellular permeability, EGF can bind its receptor and activate its pathway, where phosphorylated ERK serves as readout of EGFR activation. Thus the epithelial barrier can modulate epithelial signaling pathways.

Fig. 2.

We propose that hyperoxia, mechanical stretch, and inflammatory cytokines alter the regulation of two-pore domain potassium (K2P) channel function. This can then impact on cytokine secretion and epithelial barrier function, and this dysregulation of these proteins can contribute to the pathogenesis of acute lung injury downstream.

Fig. 3.

Cytokine activation can lead to increased free neuregulin 1 (NRG-1). Initial disruption of the epithelial barrier allows for NRG-1- human epidermal growth factor receptor 3 (HER3)-HER2 activation. The activation of this complex can lead to β-catenin tyrosine phosphorylation, which further propagates disruption of adherens junction, and alteration of the pulmonary epithelial barrier. ZO, zonula occludens; JAM, junctional adhesion molecules; CAR, coxsackie and adenovirus receptor.