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

Figures & data

Table 1 Types of Bronchial Epithelial Cells

Cell Type	Localization	Function	Reference
Basal cells	Exist as a separate layer of cells covering most of the airway basal lamina.	Progenitor cells in regeneration and repair. Attachment of columnar epithelium with the basement membrane. Basal cells are more susceptible to RV infection than suprabasal cells	Evans et al^Citation188 Hewitt and Lloyd^Citation189 Yang et al^Citation190 Morrisey^Citation191 Jakiela et al^Citation192
Suprabasal cells	Intermediate between basal and club cells.	Connected to the tight junctions to form an impermeable barrier. Adhesion is mediated by E-cadherin.	Hewitt and Lloyd^Citation189 Bukowy-Bieryllo^Citation193
Goblet cells	Line multiple mucosal surfaces, tightly packed mucin granules and surfactant proteins.	Secretion of mucus, antimicrobial proteins, chemokines and cytokines.	Knoop and Newberry^Citation194 Rogers^Citation195,Citation196 Jackson^Citation197 Yang et al^Citation198
Club cells (Clara cells)	Cells of the small airways, differentiated from basal cells in Notch-dependent manner.	Secretion of KL-6 protein, glycoproteins, and lipids. Chemical and physical protection. Able to self-renew and generate ciliated cells after injury thus, repopulating damaged airway tissue.	Rokicki et al^Citation199 Broeckaert et al^Citation200 Wang et al^Citation201 Pilon^Citation202 Tata et al^Citation203
Ciliated cells	Major cell type within the airways. Terminally differentiated and originate from club cells and/or airway basal cells regulated by Notch signaling.	Clearance of mucus and cleansing the airways of inhaled particles and pathogens. Ciliary dysfunction and ultrastructural abnormalities are closely related to asthma severity.	Hellings and Steelant^Citation5 Morimoto et al^Citation204 Guseh et al^Citation205 Whitsett^Citation3 Thomas et al^Citation206 Tilley et al^Citation207
Rare cell types
Neuroendocrine cells	Occur either as isolated cells or are organized in small clusters called neuroendocrine bodies, distributed throughout the conducting airways.	Sense airborne allergens and relay signals to stimulate immune cells and induce tissue/organ-wide responses. Increased secretory products in the regenerating airway epithelium may contribute to the development of the pathologic alterations in lung structure seen in bronchopulmonary dysplasia. Amplify allergic asthma responses.	Van Lommel et al^Citation208 Noguchi et al^Citation209 Kobayashi and Tata^Citation210 Johnson and Gergieff^Citation211 Sui et al^Citation212
Ionocytes	Tracheal epithelial cells.	Ion transport, fluid and pH regulation. Contains a C-terminal interaction domain that regulates TJ assembly and epithelial differentiation. Suggested role in pathology of cystic fibrosis by enrichment of the proton-secreting V-ATPases, important in regulating luminal pH and mucus viscosity.	Hewitt and Lloyd^Citation189 Goldfarbmuren et al^Citation213 Montoro et al^Citation214 Plasschaert et al^Citation215 Ruan et al^Citation216 Shah et al^Citation217
Hillock cells	Intermediate population between basal stem cells and differentiated luminal secretory cells. Do not contain luminal ciliated cells.	Play role in squamosus barrier function and immunomodulation. Contain a particularly high number of cycling cells and expressed markers of cellular adhesion and epithelial differentiation as well as genes associated with barrier function and immunomodulation.	Montoro et al^Citation214 Plasschaert et al^Citation215 Vieira Braga et al^Citation218 Deprez et al^Citation219 Hewitt and Lloyd^Citation189
Tuft cells (brush cells)	Chemosensory epithelial cells, bottle shaped with apical microvilli, and are expressed in a range of organs, including the gut and airway as well as in the nose, trachea and proximal airways and exist in close contact with nerve fibers.	Coordinate interactions with the external environment. Mediate communication between neuronal and immune pathways. scRNAseq has now identified two terminally differentiated Trpm5+ tuft cell populations; one is positive for Gng13 and is likely to be responsible for “taste” sensing, and the other is positive for Alox5ap, suggesting that it contributes to leukotriene synthesis. Source of IL-25 in patients with chronic rhinosinusitis with nasal polyps.	Hewitt and Lloyd^Citation189 Schneider et al^Citation220 Plasschaert et al^Citation215 Montoro et al^Citation214 Krasteva et al^Citation221 O’Leary et al^Citation222 Kohanski et al^Citation223 Patel et al^Citation224

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.

Table 2 Summary of Current and Novel Biological Therapies to Treat Asthma and Allergic Diseases

Class	Drug	Target/Mechanism	Publications
Current drugs for asthma and allergy
Inhaled glucocorticoids	Budesonide	Anti-inflammatory actions	Sekiyama et al^Citation164 Rimmer et al^Citation165 Ma et al^Citation166
	Mometasone		Doulaptsi et al^Citation167
	Fluticasone		Doulaptsi et al^Citation167
	Beclometasone
	Ciclesonide
Monoclonal antibodies	Omalizumab	Anti-IgE	Kardas et al^Citation171 Riccio et.al^Citation172 Zastrzezynska et al^Citation173 Hoshino et al^Citation174
	Mepolizumab	Anti-IL-5	Kardas et al^Citation171
	Benralizumab	Anti-IL5R, ADCC (Antibody-dependant cytotoxicity)	Kardas et al^Citation171 Laviolette et al^Citation175
	Dupilumab	Anti-IL4/13R	Kardas et al^Citation171 Bagnasco et al^Citation176
	Reslizumab	Anti-IL-5	Kardas et al^Citation171
Allergen-specific immunotherapy (AIT)	Allergen/antigen	Immune tolerance: decreases IgE-dependent activation of mast cells, tissue eosinophilia, regulatory T cells induction and local and systemic IgG, IgG4, and IgA antibodies	Globinska et al^Citation178 Shamji et al^Citation179 Akdis et al^Citation180 Yuan et al^Citation181 Hesse et al^Citation182 Hoshino et al^Citation183 Zissler et al^Citation184
Other strategies tested as treatment for asthma and allergy
Receptor blocker	Etanercept	Anti-TNF-α	Turkeli et al^Citation177
Monoclonal antibody	Bevacizumab	Anti-VEGF	Turkeli et al^Citation177
Polyamines	Spermine or spermidine	Anti-inflammatory actions	Wawrzyniak et al^Citation185
HDAC inhibitors	JNJ-26481585; sodium butyrate; siRNAs, tubastatin A HCl; PCI-34051; givinostat	Blocking histone deacetylases activity	Wawrzyniak et al^Citation55 Steelant et al^Citation159 Ren et al^Citation162 Wang et al^Citation163 Sekiyama et al^Citation164
DNMT inhibitor	SGI-1027	Blocking CpG methylation	Wawrzyniak et al^Citation153
Cannibinoids	WIN55212-2	CB1 agonist; anti-inflammatory actions	Angelina et al^Citation187

Abbreviations: AJs, adherens junctions; ALI, air-liquid interface; AIT, allergen specific immunotherapy; COX, cyclooxygenase; DC, dendritic cells; DNMTs, DNA-methyltransferases; ER, endoplasmic reticulum; EGFR, epidermal growth factor receptor; GCs, glucocorticoids; GJs, gap junctions; GM-CSF, granulocyte-macrophage colony-stimulating factor; HATs, histone acetyltransferases; HDACs, histone deacetylases; HDM, house dust mite; HBECs, human bronchial epithelial cells; IFN, interferon; IL, interleukin; JAMs, junctional adhesion molecules; LXA4, lipoxin A4; ALX, lipoxin A4 receptor; MARVEL, MAL and related proteins for vesicle trafficking and membrane link; ADAM33, metalloprotease 33; MUPP1, multi-PDZ domain protein-1; NRF2, nuclear erythroid 2-related factor 2; OVA, ovalbumin; PATJ, PALS-1-associated tight junction; PTEN, phosphatase and tensin homolog; PGE2, prostaglandin E2; PGI2, prostacyclin; PKC, protein kinase C; PP2A, protein phosphatase 2; PRG2, proteoglycan 2 expression; PCDH1, protocadherin-1; SIT, allergen specific immunotherapy; SPINK5, serine protease inhibitor Kazal-type 5; SPMs, specialized pro-resolving mediators; Th2, T helper 2; TET1, ten-eleven translocation enzyme; TSLP, thymic stromal lymphopoietin; TJs, tight junctions; TGF-β, transforming growth factor beta; TNFα, tumour necrosis factor alpha; ILC2, type 2 innate lymphoid cells; VEGF, vascular endothelial growth factor; ZO, zonula occludens.

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