The Role of Defective Epithelial Barriers in Allergic Lung Disease and Asthma Development

Abstract

The respiratory epithelium constitutes the physical barrier between the human body and the environment, thus providing functional and immunological protection. It is often exposed to allergens, microbial substances, pathogens, pollutants, and environmental toxins, which lead to dysregulation of the epithelial barrier and result in the chronic inflammation seen in allergic diseases and asthma. This epithelial barrier dysfunction results from the disturbed tight junction formation, which are multi-protein subunits that promote cell-cell adhesion and barrier integrity. The increasing interest and evidence of the role of impaired epithelial barrier function in allergy and asthma highlight the need for innovative approaches that can provide new knowledge in this area. Here, we review and discuss the current role and mechanism of epithelial barrier dysfunction in developing allergic diseases and the effect of current allergy therapies on epithelial barrier restoration.

Keywords: allergy; asthma; bronchial epithelial cells; inflammation; tight junction.

Figure 1

Bronchial epithelial cells repertoire. Common cell types: basal cells, suprabasal cells, goblet cells, club cells (Clara cells) and ciliated cells. Rare cell types: neuroendocrine cells, ionocytes, Hillock cells and Tuft cells (brush cells). Created with affinity.serif.com.

Figure 2

The junctional complex of bronchial epithelial cells. Tight junctions, adherens junction, gap junctions and desmosomes are intracellular junctions which regulate the transport of ions, water and macromolecules between tissue and lumen. TJs consist of claudins, occludin, tricellulin, and JAMs, located directly between neighboring bronchial epithelial cells. They directly interact with cytoplasmic TJs such as cingulin, MUPP1, MAGIs, non-PDZ proteins, and ZO-1, ZO-2, ZO-3 which bind directly to occludin and claudin on one end while also linking to actin fibers on the other end. Created with affinity.serif.com.

Figure 3

Mechanisms involved in a bronchial epithelial cell response to environmental factors and allergens. Airway epithelial cells are susceptible to damage as a result of exposure to allergens (house dust mite, pollen, and animal dander), pathogens (viruses, bacteria), and environmental toxins (air pollutants, cigarette smoke, ozone, detergents). Disruption of bronchial epithelium, indicated by red cell junctions, decreases the barrier integrity as evidenced by lower expression of TJs (occludin, ZO-1, E-cadherin, β-catenin, JAM and EGFR). Consequently, epithelial cells respond by secretion of cytokines IL-25, IL-33, and TSLP, which then attract other inflammatory cells like Th2 (IL-4, IL-5, IL-13), ILC2 (IL-13, IL-5), B cells, and dendritic cells (DC). Additional manifestations of respiratory disease occur in response to lipid mediators. Epithelial cells can also produce PAF and eicosanoids which have been shown to be chemotactic for neutrophils (neu), basophils (baso) and macrophages (mØ), activate eosinophils (eos) and macrophages, and alter vascular and epithelial permeability. Chronic inflammation also causes epigenetic changes in the bronchial epithelial cells by increasing DNA methylation and activating HDACs. Created with affinity.serif.com.