Claudins: Gatekeepers of lung epithelial function

Abstract

The lung must maintain a proper barrier between airspaces and fluid filled tissues in order to maintain lung fluid balance. Central to maintaining lung fluid balance are epithelial cells which create a barrier to water and solutes. The barrier function of these cells is mainly provided by tight junction proteins known as claudins. Epithelial barrier function varies depending on the different needs within the segments of the respiratory tree. In the lower airways, fluid is required to maintain mucociliary clearance, whereas in the terminal alveolar airspaces a thin layer of surfactant enriched fluid lowers surface tension to prevent airspace collapse and is critical for gas exchange. As the epithelial cells within the segments of the respiratory tree differ, the composition of claudins found in these epithelial cells is also different. Among these differences is claudin-18 which is uniquely expressed by the alveolar epithelial cells. Other claudins, notably claudin-4 and claudin-7, are more ubiquitously expressed throughout the respiratory epithelium. Claudin-5 is expressed by both pulmonary epithelial and endothelial cells. Based on in vitro and in vivo model systems and histologic analysis of lungs from human patients, roles for specific claudins in maintaining barrier function and protecting the lung from the effects of acute injury and disease are being identified. One surprising finding is that claudin-18 and claudin-4 control lung cell phenotype and inflammation beyond simply maintaining a selective paracellular permeability barrier. This suggests claudins have more nuanced roles for the control of airway and alveolar physiology in the healthy and diseased lung.

Keywords: Airway; Alveolarization; Alveolus; Cystic fibrosis; Pulmonary edema; Vascular endothelium.

Figure 1. Epithelial diversity along the respiratory tree

A. Airways are divided into four main segments: the trachea, the branching bronchi, the terminal bronchi, and the alveolar space. Each segment contains a unique mix of cell types that have specialized functions. B. The lower airway, proximal to the bifurcation of the left and right bronchus, consists of mostly ciliated cells whose main function is to sweep mucus secreted by goblet cells (blue) out of the airways. Columnar and other cells (e.g. serous cells) also contribute to the airway barrier. Basal cells (not shown) are localized to the basement membrane but do not contribute to the tight junction barrier. C. Distal to the tracheal bifurcation are bronchiolar cells that consist mainly of ciliated, columnar and club cells. Club cells secrete a specialized form of pulmonary surfactant as opposed to mucus and provide a transition zone between the airway and alveolar space. D. The alveolar space is the location of gas exchange and consists mainly of squamous type I and cuboidal type II cells. Tight junctions between these cells form at apical cell-cell interaction sites. The alveolar sac maintains surface tension through surfactant secreted by type II cells preventing alveolar collapse. E. Gas exchange occurs efficiently through type I cells, which make up the vast majority of alveolar surface area.

Figure 2. Structure of claudin ion selective pores

A. Claudin proteins are multi-pass transmembrane proteins that contain intracellular amino terminal (NT) and carboxy terminal (CT) ends, four transmembrane domains (TM1-4), an intracellular loop (IL) and an extracellular (EC) β-sheet domain where interactions between claudins occur. The EC domains consist of a small extracellular α-helix (EH) and five anti-parallel β-strands (β1–5) which form the interacting β-sheet. Based on this structural model, two variable region loops (V1 and V2) are positioned to regulate heterotypic interactions. B. The EC β-sheet (purple) interacts to form paracellular ion or metabolite selective pores (asterisks), where the specific amino acids of the β-sheets comprise the pore lining residues that confer ion/molecule selectivity. C. A simplified schematic of the paracellular pore structures (purple) formed by homo- or heterotypic interactions between claudins. Figure modified from [42] with permission.