Role of air pollutants in airway epithelial barrier dysfunction in asthma and COPD

Abstract

Chronic exposure to environmental pollutants is a major contributor to the development and progression of obstructive airway diseases, including asthma and COPD. Understanding the mechanisms underlying the development of obstructive lung diseases upon exposure to inhaled pollutants will lead to novel insights into the pathogenesis, prevention and treatment of these diseases. The respiratory epithelial lining forms a robust physicochemical barrier protecting the body from inhaled toxic particles and pathogens. Inhalation of airborne particles and gases may impair airway epithelial barrier function and subsequently lead to exaggerated inflammatory responses and airway remodelling, which are key features of asthma and COPD. In addition, air pollutant-induced airway epithelial barrier dysfunction may increase susceptibility to respiratory infections, thereby increasing the risk of exacerbations and thus triggering further inflammation. In this review, we discuss the molecular and immunological mechanisms involved in physical barrier disruption induced by major airborne pollutants and outline their implications in the pathogenesis of asthma and COPD. We further discuss the link between these pollutants and changes in the lung microbiome as a potential factor for aggravating airway diseases. Understanding these mechanisms may lead to identification of novel targets for therapeutic intervention to restore airway epithelial integrity in asthma and COPD.

FIGURE 1

Inhalation of air pollutants promotes airway epithelial barrier dysfunction. a) Healthy airway epithelium is protected against pathogens by physical junctions between the adjacent cells and by releasing innate immune HDPs. b) By exposure to airborne PM, the TJs and AJs between the AECs, including ZO-1, occludin and E-cadherin, are disrupted. Furthermore, PM induces mucociliary dysfunction by reducing cilia number, loss of cilia as well as goblet cell metaplasia leading to increased mucus production. PM entering the airway submucosa is presented to adaptive immune cells by APCs. PM-induced increase in MHCII on APCs leads to expansion of adaptive immune cells and production of inflammatory cytokines that further inflict airway epithelial barrier dysfunction. PM exposure also induces submucosal accumulation of neutrophils which may lead to barrier dysfunction by secretion of SPs. c) PM-induced barrier dysfunction is in part triggered by AhR-mediated increase in ROS generation by mitochondria and subsequent activation of EGFR and ERK or ROS-mediated increase in cytoplasmic HMGB1 and ROS-mediated increase in autophagy in AECs. Activation of EGFR either by PM-induced increase in AREG or ROS leads to disassembly in AJs by disrupting E-cadherin/β-catenin, and increased TJs permeability by Rac1/JNK-mediated disruption in ZO-1 and occludin. Activation of ERK in turn triggers airway barrier dysfunction through HER2-mediated increase in IL-6. AEC: airway epithelial cell; AhR: aryl hydrocarbon receptor; AJ: adherens junction; APC: antigen-presenting cell; AREG: amphiregulin; β-cat: β-catenin; E-cad: E-cadherin; EGFR: epidermal growth factor receptor; ERK: extracellular signal-regulated kinase; HDP: host defence proteins and peptide; HER2: human epidermal receptor 2; HMGB1: high-mobility group box 1; IFN: interferon; IL: interleukin; JNK: c-jun N-terminal kinase; MHCII: major histocompatibility complex class II; MUC5AC: mucin 5AC; OCLDN: occludin; PAH: polyaromatic hydrocarbon; PM: particulate matter; ROS: reactive oxygen species; SP: serine protease; Th: T-helper cell; TJ: tight junction; TNF: tumour necrosis factor; ZO-1: zonula occludens-1. Figure partially created with BioRender.com.

FIGURE 2

Air pollutant-induced microbial dysbiosis in airway epithelium may enhance airway epithelial permeability. a) Healthy human airway microbiome is mainly composed of Firmicutes, Proteobacteria and Bacteroidetes. b) Upon acute exposure to various air pollutants, the composition of the microbiome in the upper airways changes, with an increased abundance of Firmicutes, Bacteroidetes and Cyanobacteria in rats, while fewer Actinobacteria, Proteobacteria and Firmicutes are observed in humans. PM induces dissemination of microbiome from upper to the lower airways where it exerts pathogenic actions, as observed by the abundance of Firmicutes and Proteobacteria in the lower airways of individuals exposed to PM. PM-induced dysbiosis in lung microbiome may induce airway barrier disruption as pathogenic Firmicutes and Proteobacteria, including Streptococcus pneumoniae and Pseudomonas aeruginosa, that are known to disrupt airway barriers are overrepresented in the lower airways, which may exacerbate pre-existing epithelial damage in patients with asthma and patients with COPD. AJ: adherens junction; PM: particulate matter; TJ: tight junction. Figure partially created with BioRender.com.