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.

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

“…Epithelial cell-cell junctions bind epithelial cells into the cohesive barrier between the lumen of the epithelium and the parenchyma. Respiratory epithelial junctions have been extensively reviewed elsewhere (193)(194)(195). This section serves to summarize their function and relevance in the maintenance of epithelial barrier function and host tolerance to pulmonary infection.…”

Altered expression of a two-pore domain (K2P) mechano-gated potassium channel TREK-1 in Hirschsprung’s disease

“…A recent study reported that TREK-1 deficiency in TREK-1 KO mice resulted in increased lung damage (23). The authors proposed that the deficiency could have an impact on cytokine secretion and epithelial barrier function, and that the dysregulation of these proteins can contribute to the pathogenesis of epithelial injury.…”

Large‐conductance Ca2+‐activated K+ channel activation by apical P2Y receptor agonists requires hydrocortisone in differentiated airway epithelium

“…; Brune et al . ). Apical K + secretion mediated by BK also increases and sustains Cl − efflux following purinergic receptor stimulation and provides additional solute to increase the osmotic gradient necessary for airway hydration.…”

“…The reduced depth of the periciliary fluid layer decreased ciliary beat frequency, which could be fully restored by the addition of apical fluid. An important consequence of reduced ciliary beating and ASL volume is impaired mucus clearance, which is observed in certain airway diseases including CF, asthma and COPD (Jansen et al 1995;Livraghi & Randell, 2007;Bhowmik et al 2009;Boon et al 2014;Brune et al 2015). Apical K + secretion mediated by BK also increases and sustains Cl − efflux following purinergic receptor stimulation and provides additional solute to increase the osmotic gradient necessary for airway hydration.…”