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Year : 2013  |  Volume : 27  |  Issue : 2  |  Page : 95-101

Airway epithelial cells: Barrier and much more

Allergy and Immunology Section, CSIR - Institute of Genomics and Integrative Biology, Delhi, India

Date of Web Publication4-Jan-2014

Correspondence Address:
Naveen Arora
Room 509, Allergy and Immunology Section, CSIR - Institute of Genomics and Integrative Biology, Delhi University Campus, Mall Road, Delhi - 110 007
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Source of Support: Network Project, Council of Scientifi c and Industrial Research, Conflict of Interest: None

DOI: 10.4103/0972-6691.124390

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Airway epithelial cells were first considered as a barrier to the inhaled environmental bioparticles, but recent evidences show that they have a more vital role to play in the pathophysiology of Airway diseases. Many of the factors present in the inhaled air interact with the receptors expressed on the epithelial cells leading to their activation. Activated epithelial cells then secrete a range of mediators that help in mediating the inflammation. These mediators contain the chemokines that act as chemoattractants and recruit inflammatory cells like neutrophils, macrophages, mast cells, eosinophils, and Th-2 cells that further exacerbate the intensity of inflammation. Some of the inhaled substances like protease enzymes can also disrupt the barrier of epithelium and gain an entry to the immune cells of the body leading to their activation. Bronchial asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome represent a broad range of conditions involving pulmonary inflammation. This review takes into account the role of epithelial cells in initiating allergic reactions at mucosal surfaces.

Keywords: Allergy, asthma, bronchial epithelial cells, interleukin-25, interleukin-33, thymic stromal lymphopoietin

How to cite this article:
Kale SL, Arora N. Airway epithelial cells: Barrier and much more. Indian J Allergy Asthma Immunol 2013;27:95-101

How to cite this URL:
Kale SL, Arora N. Airway epithelial cells: Barrier and much more. Indian J Allergy Asthma Immunol [serial online] 2013 [cited 2023 Jan 29];27:95-101. Available from: https://www.ijaai.in/text.asp?2013/27/2/95/124390

  Introduction Top

A human being inhales approximately 10,000 L of air every day. The inhaled air contains a variety of potentially harmful particulate matter such as dust particles, irritants, ozone, viruses, fungi, bacteria, pollens, environmental tobacco smoke, etc. [1] The conducting airways carry inhaled air towards the alveoli situated in the lower respiratory tract where gaseous exchange takes place. The conducting airways consist of trachea, bronchi, and bronchioli and are covered with pseudostratified epithelium. Based on the functional, biochemical, and ultrastructural characteristics of the airway epithelial cells; they can be broadly grouped in three categories viz. ciliated, basal, and secretory cells. [2] The main type of cells in these groups consist of ciliated columnar cells, mucous secreting goblet cells, [3] and surfactant secreting clara cells. [4] The airway epithelium acts as a first line of defense by (i) providing a physical barrier and prevents inhaled particles from interacting with smooth muscles, blood vessels, and intraepithelial nerves; (ii) secreting mucus that traps the inhaled particulates which are then pushed towards pharynx by coordinated mucociliary movement; [5]],[[6]],[[7]] and (iii) by secreting mediators that recruit cells of innate and adaptive immune systems. It plays a key role in maintenance of lung fluid balance, secretes inflammatory mediators and proinflammatory cytokines. It also regulates the functioning of underlying airway smooth muscle cells.

Airway epithelium as a physical barrier

Under normal circumstances airway epithelium forms a relatively impermeable barrier through the formation of tight junctions with the neighboring cells. The tight junctions are composed of peripheral membrane proteins (claudins 1-5, occludins, and zonula occludens 1-3) and transmembrane proteins (β-catenin, E-cadherin, and junctional adhesion proteins) [8] that interact to form tight seals with the neighboring cells. Tight junctions play a major role in regulating paracellular permeability [9] and partitions the apical surface from that of the basolateral surface of the epithelial cell. Tight junctions also help in cell-cell communication. Desmosomes, hemidesmosomes, and adherens junctions also help in maintenance of epithelial cell integrity through cell-cell and cell-extracellular matrix interactions.

Chemical barrier

Nicholas et al., in 2006 showed that the human-induced sputum is a complex secretion comprising 191 different proteins. [10] Many of these proteins present in the mucus act as effector molecules of innate immune system that aid to remove potentially harmful organisms from the inhaled air. These proteins include defensins, cathelicidins, lactoferrin, lysozyme, palate, lung, and nasal epithelium clones, secretory leucocyte protease inhibitor, secretory phospholipases A2, etc., These antimicrobial peptides produced by epithelial cells act as antimicrobial agents against the invading pathogens like gram positive and gram negative bacteria, enveloped viruses, and fungi. [11]

Airway epithelial cells are exposed continuously to endogenous and exogenous reactive oxygen species/reactive nitrogen species (ROS/RNS). Environmental pollutants such as nitrogen dioxide, ozone, cigarette smoke, and automobile exhaust contain lot of oxidants. [12] Particulate matter present in the inhaled environment such as ambient air dust and residual oil fly ash contain traces of transition metals that are capable of generating ROS in the airways. [13] Endogenous reactive species are generated by airway epithelial cells when they are exposed to proinflammatory cytokines such as tumor necrosis factor (TNF)-α. [14] TNF-α upregulates the expression of an enzyme called xanthine oxide that generates superoxide anion radical and H 2 O 2 from the inhaled oxygen. [15] Airway epithelial cells interact with these reactive species in both enzymatic and nonenzymatic ways. Enzymes such as superoxide dismutase, catalase, and glutathione cycle enzymes such as glutathione peroxidase along with nonenzymatic antioxidants like β-carotene, uric acid, vitamins C and E, and thiols function to protect the airways from the reactive species. Thus, these enzymes and nonenzymatic antioxidants form a barrier for the inhaled oxidants and prevent their harmful interaction with the airway epithelial cells. Mucus owing to the presence of sugar moieties present, has antioxidant properties and can scavenge hydroxyl radicals and H 2 O 2 . [12]

Mucus is a complex mixture of water, proteins, and glycoproteins. Mucin comprises a large fraction of mucus secretion and is composed mainly of MUC5AC and MUC5B glycoproteins with a small amount of MUC2. [16],[17] Together these glycoproteins confer viscoelastic properties to the mucus. These glycoproteins form a structural framework that functions as a barrier. The mucins are variously glycosylated and this glycosylation pattern may help them to interact with microorganisms, trap them, and remove them through mucociliary clearance. [18]

  Activated Epithelial Cells Secrete a Variety Of Mediators, Proinflammatory Cytokines, Growth Factors, and Adhesion Molecules Top

Traditionally airway epithelial cells were considered as an inert barrier between the inhaled air and the inner tissues of airway wall. However, many studies have shown that airway epithelium is critical and plays a major role in many airway functions. [19]],[[20]],[[21] Recent studies have shown that airway epithelium is active metabolically and secrets a wide variety of pharmacologically and immunologically active compounds that regulate the airway inflammatory process, in addition it also plays a pivotal role in recruitment and activation of inflammatory cells viz. eosinophils, neutrophils, etc., through the expression of adhesion molecules. [22]

Arachidonic acid metabolites

Bronchial epithelium has shown to express enzymes involved in arachidonic acid metabolism such as 5-, 12-, and 15-lipoxygenase, cyclooxygenase, and monooxygenase. [23] Bronchial epithelium regulates the underlying smooth muscle cells and secretion of mucus by goblet cells by secreting various lipid mediators. Human bronchial epithelial cells can convert arachidonic acid into an array of inflammatory mediators by two different pathways: Lipoxygenase and cyclooxygenase pathway. [24] In the lipoxygenase pathway that dominates in human airway cells, arachidonic acid is oxygenated to 15-hydroxyeicosatetraenoic (HETE) acid, 12S-dihydroxyeicosatetraenoic (DHETE), 5-HETE, and di-HETE. [25]],[[26]],[[27] However, 15-HETE is produced in abundance and high levels of the same were observed in the lung epithelium of asthmatics and chronic bronchitis. [25] It is believed that 15-HETE activates 5-lipoxygenase in mast cells. [28] Marom et al., [29] showed that 15-HETE was most active in secreting mucus from human bronchial cell line. In cyclooxygenase pathway arachidonic acid is metabolized by the airway epithelial cells to produce prostaglandin (PG) E 2 , PGI 2 , PGF2α, and thromboxane A 2 (TxA 2 ) with PGE 2 produced in more amounts. Many of the evidences suggest that PGE 2 acts as a bronchoprotective agent and show inhibitory effect on smooth muscle contraction, mucus secretion by goblet cells, and intraepithelial nerve activation. [30],[31] Epithelium also produces prostacyclins and TxA 4 which acts as a potent platelet aggregating factor. [32]

Other mediators

Platelet activating factor is another lipid mediator produced by airway epithelial cells and may affect an increase in vascular permeability and recruitment of neutrophils and eosinophils.

Along with lipid mediators, airway epithelial cells can also produce peptide mediators like endothelin, [33] vasopressin, and substance P. [34] Although a number of cells like macrophages, endothelial cells, and mast cells produce endothelins; bronchial epithelium acts as a principle site for endothelial expression. [35] Endothelin family of proteins consists of three closely related peptides endothelin-1, endothelin-2, and endothelin-3 that can act as bronchoconstrictors, vasodialators, and increase mucus secretion and proliferation of smooth muscles. [36],[37] Several studies suggested that endothelin serves in pathogenesis of asthma as its amount in bronchoalveolar lavage fluid (BAL) is more in asthmatics than the normal subjects. [38],[39] Substance P increases vascular permeability, mucus secretion, bronchoconstriction, and activates macrophages and eosinophils.

Proinflammatory cytokines

There is an increasing evidence of proinflammatory cytokine expression by the epithelial cells and epithelial cell lines in vitro. These include colony stimulating factors (CSFs), chemoattractants, pleiotrophic cytokines, and growth regulators. Evidences suggest there is increased production of these cytokines in airway inflammation. Disruption of epithelial cell barrier and activation of certain receptors on the surface of epithelial cells causes increased production of these cytokines. The CSFs produced by epithelium include granulocyte macrophage CSF (GM-CSF), M-CSF, and CSF-1. [40] Of these, GM-CSF is the most studied and is a potent mediator of airway inflammation as indicated by the studies carried out by Su et al., which demonstrated the correlation between GM-CSF production and airway infiltration of activated eosinophils. [41] GM-CSF also acts as a chemoattractant for neutrophils and together with G-CSF increases the survival of both neutrophils and eosinophils. [42]],[[43]],[[44] Airway epithelial cells also produce a variety of chemoattractants when activated, which compromises chemokines of C-X-C or α family, and C-C or β-family. Among α family of chemokines interleukin (IL)-8 is produced in large amounts along with GRO-α and GRO-β by cultured human epithelial cells. IL-8 is a potent chemoattractant of neutrophils, activated eosinophils, and subsets of T-lymphocytes. GRO-α and GRO-β also act as chemoattractants for neutrophils. Among the β-family of chemokines regulated on activation, normal T cell expressed and secreted (RANTES) a potent chemotaxin of eosinophils and monocyte chemoattractant protein (MCP)-1 helps in activation and chemotaxis of eosinophils. [45] Other cytokines produced by epithelial cells include IL-6, TNF-α, and IL-1β. [46] These cytokines are pleiotropic in nature and affect a variety of target cells.

Nitric oxide

Nitric oxide plays an important role in cell signaling and is thought to be involved in the pathophysiology of a number of diseases including airway diseases. [47],[48] NO is produced by the enzyme nitric oxide synthase (NOS) from the guanidine nitrogen of L-arginine. NOS exist in three isoforms of which two are constitutive NOS (cNOS) and one is inducible (iNOS). [49] Although airway epithelial cells express all three isoforms of NOS, NO is produced through the action of inducible NOS called as NOS-2. There is an evidence that iNOS is expressed more in the epithelial cells of asthmatics than normal individuals. [50] Though NO is exhaled by normal individuals its concentration is markedly increased in asthmatic patients. [51] cNOS is calcium dependent, whereas iNOS is calcium independent and is expressed in response to proinflammatory cytokines such as IL-1β, TNFα, and interferon (IFN)-γ. [52] Inhalation of high amounts of NO causes bronchodialation in asthmatic patients which suggests that NO might play a beneficial role in asthma, but there are also reports that NO is vasodilator and increases blood flow to lung causing plasma exudates. NO can suppress T helper (Th1) subset of cells and therefore favor Th2 cell activation which further mediates the inflammatory response by secreting IL-4, IL-5, and IL-13. [53]

Thymic stromal lymphopoietin (TSLP)

Epithelial cells present in the lungs, gut, and skin produce TSLP [54] when they encounter viruses, bacteria, or pathogenic fungi. [55] Although the levels of TSLP are high in asthma patients, the mechanisms underlying it are not well-elucidated. However, Kouzaki and coworkers [56] revealed that increase in TSLP levels is due to the activation of PAR2 receptors by protease allergens. TSLP is an IL-7 like cytokine and triggers intracellular signaling by binding to its receptor TSLPR which is primarily located on dendritic cells (DCs). Unlike mouse TSLP which supports development and differentiation of B-cells and proliferation of T-cells, human TSLP activates myeloid DCs (mDCs). [57] TSLP activates mDCs, but does not stimulate them to produce Th1 polarizing cytokines such as IL-12, TNF, and IL-1β. [58] Instead it increases the secretion of eotaxin and IL-8 by mDCs that have a chemoattractive effect on eosinophlis and neutrophils respectively, [59] and thymus and activation-regulated chemokine (TARC) and macrophage derived chemokine (MDC) that attract Th2 cells. [60] TSLP activated mDCs then activate naοve CD4 + T-cells to produce the proinflammatory cytokines like IL-4, IL-5, IL-13, and TNF [as shown in [Figure 1]] and downregulates expression of IL-10 and IFN-γ. [58] mDCs activated Th2 cells differ from that of the conventional Th2 cells as they produce high levels of TNF in contrast to conventional Th2 cells and so Liu proposed that these cells to be called as inflammatory Th2 cells. [60]
Figure 1: TSLP is produced by the epithelial cells when they encounter viruses, allergens or fungal pores. The thymic stromal lymphopoietin then activates mDCs. Activated mDCs then produce MDC, thymus and activation-related chemokine, eotaxin, and IL-8. MDC and TARC act as chemoattractants for Th2 cells where as eotaxin and IL-8 recruit eosinophils and neutrophils, respectively to the site of inflammation. mDC also activates and helps in the differentiation of naïve Th cell towards Th2 type cells and activate them to secrete IL-4, IL-5, IL-13, and TNF-α

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Interlukin-25 and interlukin-33

Though produced majorly by Th2 cells it is demonstrated that following the exposure to allergens, human bronchial cell lines secrete IL-25. [61] Elevated levels of IL-25 were found in the tissue biopsies of asthma patient suggesting its role in phathophysiology of asthma. [62] IL-25 is a member of IL-17 family and is also known as IL-17F. [63] Overexpression of IL-25 results in polarization of Th response towards Th-2 type and induces secretion of IL-3, IL-4, and IL-13. [64] IL-25 has been also shown to act on the survival of eosinophils with their recruitment into the airways [65] and selectively increase the expression of intercellular adhesion molecule (ICAM)-1 in eosinophils. [66] IL-33 is a member of IL-1 cytokine family. IL-33 like IL-25 promotes Th-2 response [67] and mediates release of Th-2 cytokines IL-5 and IL-13 suppressing the INF-γ. IL-33 also acts as a chemoattractant to Th-2 cells. Its helps in the differentiation of CD34 + into mast cells and release of TNF-α, IL-6, IL-1, and MCP1 from bone marrow derived mast cells. [68]

Growth factors and adhesion molecules

Increase in the expression of adhesion molecules in the airway epithelial cells may help in the recruitment of inflammatory cells to the site of airway damage that will lead to further damage to epithelial cells increasing airway reactivity. [69] Airway epithelial cells express ICAM-1 on their surfaces under basal conditions in culture. [70] When epithelial cells are exposed to TNF-α, they show an increase in the expression of surface ICAM-1. This increase in the expression increased with the concentration and the time of exposure of TNF-α. [71] Eosinophils bind to ICAM-1 and are recruited to the site of inflammation.

  Interaction of Airway Epithelial Cells with Allergens Top

Physical, chemical, and biological activity of the inhaled particles can damage the airway epithelial cells. Tissue biopsies obtained from asthma patients and from the patients of chronic obstructive pulmonary disease (COPD) and rhinitis show abnormally damaged airway epithelium with goblet cell metaplasia and eosinophil recruitment. This indicates that although a tightly regulated barrier of airway epithelial cells exists, allergens are able to disrupt these physical and chemical barriers gaining an access to the inner tissue and mediate inflammatory reactions. Some of the allergens present in the inhaled air like the allergens from Dermatophagoides pteronyssinus, Periplanata americana, and those from pollens and fungi are proteases. [72],[73],[74],[75] These allergens breach the barrier of epithelial cells by disrupting the occludin proteins of tight junctions by their proteolytic activity and gain an access to the inner tissues of airway wall through paracellular pathway. [76],[77] Various studies have shown an increase in permeability of airway epithelial cells to C 14 -mannitol in vitro, which increases with the concentration of the proteolytic allergen and this increase in permeability is due to disruption of tight junctions. [76] They also showed an increase in epithelial cell desquamation exposed to these allergens in a time- and dose-dependent manner. [78] Cell culture experiments with human bronchial epithelial derived cell lines, A549, and BEAS-2B demonstrated the release of proinflammatory cytokines, CSFs, and lipid and peptide mediators; when exposed to proteolytic allergens [Figure 2].
Figure 2: Schematic diagram showing the interaction of environmental particles with the airway epithelium and subsequent production of mediators and proinflammatory cytokines by the activated epithelium

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  Receptors on Epithelial Cells Playing Crucial Role in Inflammation Top

Protease activated receptors

Among the allergens with enzymatic activity, proteases are the most common. The allergens from house dust mite and those isolated from cockroaches and pollen possess protease activity and these allergens activate the epithelial cells of airways by interacting with PARs. [79] PARs are a family of G protein coupled receptors that are activated on cleavage by proteases within the extracellular N-terminal region to form a tethered ligand that binds intramolecularly and activates the receptor. Four PARs have been identified. [80],[81],[82] PAR-1, -3, and -4 are activated by thrombin, whereas PAR-2 is activated by trypsin like enzymes. Epithelial cells throughout the body express PAR-2, [83] whereas PAR-1 is expressed only by airway epithelial cells but not by gastrointestinal and pancreatic epithelium. [84],[85] No study has been carried out to elucidate the presence of PAR-3 and -4 on airway epithelium. Activation of PAR-1, -2, and -4 stimulate the human respiratory epithelial cells to secrete proinflamatory cytokines like IL-6 and IL-8. [79]

Toll like receptors

Airway epithelium is known to express (TLRs). These pattern recognition receptors bind to their ligand with an extracellular domain and transmit the signal via activation of an array of adaptor proteins leading to the activation of nuclear factor (NF)-κB or IFN regulatory factor 3 and 7 (IRF 3/7). This finally leads to the expression of an array of proteins such as IFN, antimicrobials, chemokines, and proinflammatory cytokines. Hammad and coworkers [86] showed that TLR expression and activation on airway structural cells is necessary for the production of TLSP, IL-25, IL-33, and GMCSF after exposure to HDM extracts.

  Conclusion Top

Airway epithelium is the first to encounter the inhaled environmental particles and possess a barrier to these particles and prevents their interaction with rest of the body. It is now known that airway epithelium is more than just a barrier and plays a vital role in the pathogenesis of a variety of airway inflammatory diseases. Detail knowledge of interaction of the environmental particles with the airway epithelium and subsequent mechanisms underlying the activation of epithelial cells to produce and secrete an array of factors that mediate airway inflammation is required for developing new generation therapies that will curb the disease and not just the symptoms.

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