Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD

Abstract

The airway epithelium comprises of different cell types and acts as a physical barrier preventing pathogens, including inhaled particles and microbes, from entering the lungs. Goblet cells and submucosal glands produce mucus that traps pathogens, which are expelled from the respiratory tract by ciliated cells. Basal cells act as progenitor cells, differentiating into different epithelial cell types, to maintain homeostasis following injury. Adherens and tight junctions between cells maintain the epithelial barrier function and regulate the movement of molecules across it. In this review we discuss how abnormal epithelial structure and function, caused by chronic injury and abnormal repair, drives airway disease and specifically asthma and chronic obstructive pulmonary disease (COPD). In both diseases, inhaled allergens, pollutants and microbes disrupt junctional complexes and promote cell death, impairing the barrier function and leading to increased penetration of pathogens and a constant airway immune response. In asthma, the inflammatory response precipitates the epithelial injury and drives abnormal basal cell differentiation. This leads to reduced ciliated cells, goblet cell hyperplasia and increased epithelial mesenchymal transition, which contribute to impaired mucociliary clearance and airway remodelling. In COPD, chronic oxidative stress and inflammation trigger premature epithelial cell senescence, which contributes to loss of epithelial integrity and airway inflammation and remodelling. Increased numbers of basal cells showing deregulated differentiation, contributes to ciliary dysfunction and mucous hyperproduction in COPD airways. Defective antioxidant, antiviral and damage repair mechanisms, possibly due to genetic or epigenetic factors, may confer susceptibility to airway epithelial dysfunction in these diseases. The current evidence suggests that a constant cycle of injury and abnormal repair of the epithelium drives chronic airway inflammation and remodelling in asthma and COPD. Mechanistic understanding of injury susceptibility and damage response may lead to improved therapies for these diseases.

Keywords: COPD; asthma; barrier; cell junctions; epithelium; injury; permeability; repair.

Figure 1

Changes to the intercellular junctions in asthma and COPD. In the asthmatic airway, after exposure to pathogens, inflammatory cytokines and the influx of inflammatory cells cause an increase in Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5) expression on the apical of surface of the cells. These cytokines and inflammatory cells, also cause a loss of vital gap junction, adherens junction and of barrier forming tight junction proteins. A thickened basement membrane is a feature seen in the asthmatic airway, meaning that epithelial cell attachment to the membrane is not altered, but the cell-cell contact is reduced. Taken together this induces epithelial shedding and denudation, reduced barrier integrity and increased permeability in asthma. In the COPD airway, continued cigarette smoke exposure causes a redistribution of adherens junction proteins, namely E-cadherin and β-catenin, reduced tight junction protein expression through abnormal phosphorylation. Unlike the asthmatic airway, the basement membrane is fragmented, causing reduced binding of the cells to the basement membrane.

Figure 2

Effect of chronic inflammatory cells and cytokines on barrier function and integrity in asthma. Exposure of the airway to pathogens causes the release of epithelial cell alarmins such as TSLP, IL-25 and IL-33. The alarmins activate Th2 inflammatory cells that release the IL-4, IL-5 and IL-13 cytokines. These cytokines play a role in driving the symptoms seen in asthma such as plasma cell activation, eosinophil expansion and airway hyper-responsiveness. On a cellular level, the IL-5 induced eosinophil expansion interacts with the epithelial barrier and causes tight junction (TJ) disruption through reduction of barrier forming claudins and mast cell degranulation. IL-4 and IL-13 inhibit the expression of TJ and adherens junction (AJ) genes E-cadherin, occludin and ZO-1. These cytokines also induce goblet cell hyperplasia and defective basal cell repair causes impaired barrier function and loss of ciliated epithelial cells.

Figure 3

Epithelial changes in COPD. Cigarette smoke, reactive oxygen species, viral infection and acute inflammation leads to loss of ciliated epithelial cells and squamous metaplasia. Persistent exposures and chronic inflammation lead to basal cell hyperplasia, goblet cell hyperplasia and reduced ciliation.