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Breakdown in epithelial barrier function in patients with asthma: Identification of novel therapeutic approaches

2009; Elsevier BV; Volume: 124; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2009.05.037

1097-6825

Emily J. Swindle, Jane Collins, Donna E. Davies,

Allergic Rhinitis and Sensitization

The bronchial epithelium is pivotally involved in the provision of chemical, physical, and immunologic barriers to the inhaled environment. These barriers serve to maintain normal homeostasis, but when compromised, the immunologic barrier becomes activated to protect the internal milieu of the lung. We discuss what is currently understood about abnormalities in these barrier functions in patients with asthma and consider novel therapeutic opportunities that target this key structure. The bronchial epithelium is pivotally involved in the provision of chemical, physical, and immunologic barriers to the inhaled environment. These barriers serve to maintain normal homeostasis, but when compromised, the immunologic barrier becomes activated to protect the internal milieu of the lung. We discuss what is currently understood about abnormalities in these barrier functions in patients with asthma and consider novel therapeutic opportunities that target this key structure. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: July 2009. Credit may be obtained for these courses until June 30, 2011.Copyright Statement: Copyright © 2009-2011. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Authors: Emily J. Swindle, PhD, Jane E. Collins, PhD, and Donna E. Davies, PhDActivity Objectives1. To understand the role of the bronchial epithelium as a chemical, physical, and immunologic barrier to the inhaled environment.2. To recognize abnormalities in barrier function in patients with asthma.3. To recognize potential therapeutic approaches to restore barrier function.Recognition of Commercial Support: This CME activity is supported by an educational grant from Merck & Co., Inc.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: D. E. Davies is a founder of and consultant for Synairgen Research Ltd and a shareholder in Synairgen plc. The rest of the authors have declared that they have no conflict of interest.GlossaryANTIOXIDANTSantioxidants are molecules capable of slowing or preventing the oxidation of other molecules by removing free radical intermediates. They are separated into hydrophilic or hydrophobic antioxidants depending on whether they are soluble in water or in lipids, respectively. Generally, hydrophilic antioxidants react with oxidants in the cell cytosol and the blood plasma, whereas hydrophobic antioxidants protect cell membranes from lipid peroxidation.ATOPYAtopy is most commonly defined by increased levels of total and allergen-specific IgE in the serum, leading to positive skin prick test responses to common allergens. Atopy also refers to the genetic tendency for the classic allergic diseases: atopic dermatitis, allergic rhinitis (hay fever), and asthma.BRONCHIAL HYPERRESPONSIVENESSBronchial hyperresponsiveness is also known as airway hyperreactivity. It is an exaggerated constriction of the bronchioles or small airways of the lung in response to physical, chemical, or pharmacologic stimuli. It is typically assessed based on a bronchial challenge test with methacholine or histamine. Bronchial hyperresponsiveness is a hallmark of asthma but also occurs in subjects with chronic obstructive pulmonary disease.COMPLEMENTComplement is a biochemical cascade of more than 20 proteins that aid in eliminating pathogens as part of the innate immune response. The complement cascades function to (1) lyse cells, bacteria, and viruses; (2) promote phagocytosis of pathogens by means of opsonization; (3) bind to complement receptors to trigger downstream events; and (4) remove immune complexes. The classical complement pathway, alternative complement pathway, and mannose-binding lectin pathway carry out these functions.DENDRITIC CELLDCs are immune cells that take up, process, and present antigen to other immune cells, namely T and B cells in lymphoid tissue. These antigen-presenting cells are primarily found in tissue that serves as an entry point for antigen (ie, skin, lungs, and intestines). DCs are derived from hemopoietic bone marrow progenitors and can be plasmacytoid (pDC) or myeloid (mDC).FILAGGRINFilament aggregating protein (filaggrin) is a key protein that binds to and causes the aggregation of keratins (K1/10). Loss-of-function (null) mutations in the gene encoding filaggrin (FLG) result in impaired skin barrier function (ie, ichthyosis vulgaris, atopic dermatitis, or both) and are strongly associated with the development of asthma in patients with atopic dermatitis. R501X and 2284del4 are the most common mutations in the white population, with a prevalence of approximately 7% to 10%.HAPLOTYPEA haplotype is a combination of alleles within close proximity on the same chromosome that tend to be inherited together. It can range from as few as 2 loci or as much as an entire chromosome depending on the number of recombination events.LAMINA PROPRIAThe lamina propria is part of the mucosa, which lines the respiratory tract, the gastrointestinal tract, and the urogenital tract. More specifically, the lamina propria is a thin layer of loose connective tissue that, combined with the epithelium, forms the mucosa.MAST CELLMCs reside in various tissues throughout the body and contain histamine and heparin-rich granules. Degranulation can be initiated by means of direct injury, cross-linking of IgE receptors, or activated complement proteins. In addition to allergy and anaphylaxis, MCs exhibit a protective role by being involved in wound healing and defense against pathogens.MUCINMucins are a class of approximately 19 proteins produced by epithelial tissues. The aminoterminal and carboxyterminal regions of mucin proteins are lightly glycosylated and rich with cysteines to facilitate the formation of disulfide linkages. The central region of mucin proteins is primarily saturated with O-linked oligosaccharides. Increased mucin production is seen in patients with asthma, bronchitis, and chronic obstructive pulmonary disease, with MUC5AC and MUC5B as the most prevalent.POLYMORPHISMA polymorphism is also referred to as a single nucleotide polymorphism (SNP) and is a genomic variation occurring when a single nucleotide is different between members of the same species. SNPs can alter genomic DNA-coding sequences, thereby potentially altering amino acid sequences and protein production. In genetic studies SNPs are often assigned an allelic frequency and can be used as biomarkers to determine whether a patient has a genetic predisposition for a particular disease.REACTIVE OXYGEN SPECIESReactive oxygen species are oxygen centered free radicals or reactive non-radical compounds that are generated enzymatically or form as a byproduct of oxygen metabolism and can increase dramatically in times of environmental stress. Reactive oxygen species can induce significant cell damage by damaging DNA, oxidizing fatty acids in lipids, oxidizing amino acids, and inactivating specific enzymes.TIGHT JUNCTIONA TJ is a closely associated area of 2 cells with membranes that join together, forming a virtually impermeable barrier to fluid. TJs prevent the passage of molecules and ions through the space between cells, thereby forcing them to enter the cells by means of diffusion or active transport to pass through the tissue. Movement of membrane proteins between the apical and basolateral surfaces of the cell is additionally blocked, preserving transcellular transport.THYMIC STROMAL LYMPHOPOIETINTSLP is produced mainly by nonhematopoietic cells as fibroblasts, epithelial cells, and different types of stromal or stromal-like cells. By signaling through the heterodimeric receptor complex of TSLP receptor and IL-7 receptor α, TSLP triggers the release of T cell–attracting chemokines from monocytes and the maturation of DCs. Expression of TSLP is enhanced under atopic conditions, potentiating a TH2 response.TOLL-LIKE RECEPTORSTLRs are a family of membrane glycoproteins that play an important role in the innate immune response by recognizing pathogen-associated molecular patterns, molecules that are shared by pathogens but distinguishable from host molecules. Thirteen TLRs have been identified in human subjects and mice collectively and pair with an adaptor molecule for signaling. TLRs are members of a larger superfamily that includes the IL-1 receptors because of a conserved Toll/IL-1 receptor domain in the cytoplasmic tail.The Editors wish to acknowledge Seema Aceves, MD, PhD, for preparing this glossary.Asthma is an inflammatory disorder of the conducting airways, which undergo distinct structural and functional changes, leading to nonspecific bronchial hyperresponsiveness and airflow obstruction that fluctuates over time. It is among the most common chronic conditions in Western countries, affecting 1 in 7 children and 1 in 12 adults. Although at one time considered a single disease entity, asthma subphenotypes are now recognized with differing pathology, clinical expression, responses to treatment, and long-term outcomes.1Anderson G.P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease.Lancet. 2008; 372: 1107-1119Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar Most asthma exhibits a TH2-type inflammatory response with upregulation of cytokines of the IL4 gene cluster linked to atopy; however, the indistinguishable pathologic features of nonallergic and allergic asthma and the fact that the great majority of atopic subjects do not have asthma2Pearce N. Pekkanen J. Beasley R. How much asthma is really attributable to atopy?.Thorax. 1999; 54: 268-272Crossref PubMed Google Scholar emphasizes that asthmatic airway inflammation and remodeling can occur independent of atopy.3Turato G. Barbato A. Baraldo S. Zanin M.E. Bazzan E. Lokar-Oliani K. et al.Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma.Am J Respir Crit Care Med. 2008; 178: 476-482Crossref PubMed Scopus (64) Google ScholarWe have previously proposed that allergic-type inflammation and aberrant epithelial injury/repair mechanisms were parallel phenomena leading to different asthma subtypes4Holgate S.T. Davies D.E. Lackie P.M. Wilson S.J. Puddicombe S.M. Lordan J.L. Epithelial-mesenchymal interactions in the pathogenesis of asthma.J Allergy Clin Immunol. 2000; 105: 193-204Abstract Full Text Full Text PDF PubMed Google Scholar that involved activation of the epithelial-mesenchymal trophic unit, which controls the local tissue microenvironment.5Davies D.E. Wicks J. Powell R.M. Puddicombe S.M. Holgate S.T. Airway remodelling in asthma—new insights.J Allergy Clin Immunol. 2003; 111: 215-225Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar We postulated that in patients with asthma, epithelial susceptibility to damage by environmental agents results in signals that act on the underlying mesenchyme to propagate and amplify inflammatory and remodeling responses in the submucosa. Based on current understanding, many of the persistent inflammatory and structural responses in patients with asthma, including airway allergen sensitization in genetically susceptible individuals, could follow from a defective epithelium, leading to a chronic wound response to repeated environmental injury. Similar mechanisms are now thought to operate in other allergic diseases, leading to enhanced allergen sensitization. Examples include eczema, in which polymorphisms in the filaggrin gene affect skin permeability,6O'Regan G.M. Sandilands A. McLean W.H. Irvine A.D. Filaggrin in atopic dermatitis.J Allergy Clin Immunol. 2008; 122: 689-693Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar and food allergy, in which infection or stress can increase intestinal permeability.7Heyman M. Gut barrier dysfunction in food allergy.Eur J Gastroenterol Hepatol. 2005; 17: 1279-1285Crossref PubMed Scopus (35) Google ScholarThe finding that many novel asthma susceptibility genes identified from hypothesis-independent approaches8Cookson W. The immunogenetics of asthma and eczema: a new focus on the epithelium.Nat Rev Immunol. 2004; 4: 978-988Crossref PubMed Scopus (234) Google Scholar are expressed in the epithelium helps place it at the center of asthma pathogenesis. Furthermore, the most frequent environmental risk factors for developing, exacerbating, and prolonging asthma, namely biologically active allergens, air pollutants, environmental tobacco smoke, and respiratory viruses,9Sly P.D. Boner A.L. Bjorksten B. Bush A. Custovic A. Eigenmann P.A. et al.Early identification of atopy in the prediction of persistent asthma in children.Lancet. 2008; 372: 1100-1106Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 10Sears M.R. Epidemiology of asthma exacerbations.J Allergy Clin Immunol. 2008; 122: 662-668Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 11Martinez F.D. Development of wheezing disorders and asthma in preschool children.Pediatrics. 2002; 109: 362-367PubMed Google Scholar act on the epithelium, thereby strengthening the case for a dynamic interaction between the epithelium and formed elements of the airways in the development of asthma subphenotypes.1Anderson G.P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease.Lancet. 2008; 372: 1107-1119Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar The purpose of this review is to consider aspects of the barrier properties of the airway epithelium and to discuss what is currently understood about abnormalities in these barrier functions in patients with asthma, as well as other inflammatory diseases, at the mucosal surfaces. Finally, we will consider novel therapeutic approaches that target this key structure.The chemical barrier of the airwaysEach day, the inner surface of the airways is exposed to at least 10,000 L of air, which can contain many particulates, including dusts and microorganisms, as well as noxious gases.12van der Schans C.P. Bronchial mucus transport.Respir Care. 2007; 52: 1150-1156PubMed Google Scholar These environmental challenges are largely overcome by an efficient filtering system and innate defense mechanisms without the need for an inflammatory response. Within this system, the first line of defense in the lower airways is provided by the bronchial secretions that form both a chemical barrier that detoxifies noxious particles and a physical barrier that traps inhaled particles and, through the action of the mucociliary escalator, continuously transports them from the lower airways to the oropharynx.Mucus and host defenseRespiratory mucus is a complex secretion, as highlighted by a recent proteomic analysis that identified 191 different proteins in human induced sputum.13Nicholas B. Skipp P. Mould R. Rennard S. Davies D.E. O'Connor C.D. et al.Shotgun proteomic analysis of human-induced sputum.Proteomics. 2006; 6: 4390-4401Crossref PubMed Scopus (55) Google Scholar The main component of these secretions are the large, highly charged mucin molecules (predominantly MUC5B and MUC5AC), which cross-link to form a viscoelastic gel. These multifunctional glycoproteins provide the structural framework of the mucus barrier, prevent dehydration of the epithelial surface, present carbohydrate ligands to sequester pathogens, and can bind to other secreted components, such as host-protective proteins and peptides.14Thornton D.J. Rousseau K. McGuckin M.A. Structure and function of the polymeric mucins in airways mucus.Annu Rev Physiol. 2008; 70: 459-486Crossref PubMed Scopus (169) Google Scholar Other soluble factors, such as complement, immunoglobulins, surfactant proteins, Clara cell proteins, and palate, lung, and nasal epithelium clones (PLUNCs) also contribute to innate defense. PLUNCs are structural homologues of LPS-binding protein and the bacterial permeability–increasing protein, both of which are known mediators of host defense against gram-negative bacteria.15Bingle C.D. Gorr S.U. Host defense in oral and airway epithelia: chromosome 20 contributes a new protein family.Int J Biochem Cell Biol. 2004; 36: 2144-2152Crossref PubMed Scopus (54) Google Scholar Other antimicrobial components include defensins, cathelicidins, lysozyme, lactoferrin, secretory phospholipase A2, and secretory leukocyte protease inhibitor, which can selectively disrupt bacterial cell walls and membranes, sequester microbial nutrients, or act as decoys for microbial attachment.16Herr C. Shaykhiev R. Bals R. The role of cathelicidin and defensins in pulmonary inflammatory diseases.Expert Opin Biol Ther. 2007; 7: 1449-1461Crossref PubMed Scopus (27) Google Scholar These host defense molecules can arise from several cellular sources, including airway epithelium, serous gland cells, and myeloid cells, such as neutrophils, macrophages, and lymphoid natural killer cells, or from the circulation. Although β-defensins have antibacterial properties, they are induced in response to viral infection and appear to exert direct antiviral actions against some enveloped viruses and also can impair viral infection.17Proud D. The role of defensins in virus-induced asthma.Curr Allergy Asthma Rep. 2006; 6: 81-85Crossref PubMed Scopus (8) Google Scholar Specific polymorphisms and haplotypes in the human β-defensin 1 gene have been associated with asthma and atopy18Leung T.F. Li C.Y. Liu E.K. Tang N.L. Chan I.H. Yung E. et al.Asthma and atopy are associated with DEFB1 polymorphisms in Chinese children.Genes Immun. 2006; 7: 59-64Crossref PubMed Scopus (35) Google Scholar; however, no studies have analyzed levels of β-defensin 1 in airways secretions from asthmatic subjects.Oxidant defense in patients with asthmaThe bronchial epithelium is particularly vulnerable to the effects of ambient oxygen, as well as exogenous oxidants from air pollutants (eg, ozone, sulfur dioxide, oxides of nitrogen, and diesel exhaust particles) that are particularly associated with increased risk of development and exacerbation of asthma. The bronchial secretions contain an array of efficient antioxidant mechanisms for the primary protection of the airways.19Kelly F.J. Vitamins and respiratory disease: antioxidant micronutrients in pulmonary health and disease.Proc Nutr Soc. 2005; 64: 510-526Crossref PubMed Scopus (31) Google Scholar These include reduced glutathione, antioxidant enzymes, uric acid, vitamins C and E, and proteins such as albumin, transferrin, ceruloplasmin, and lactoferrin, which are capable of binding free iron and other metals that might generate reactive oxygen species, as well as the mucins themselves.In patients with asthma, exposure to air pollutants or endogenously produced reactive oxygen species or reactive nitrogen species appears to lead to oxidative stress, which can result in direct damage to proteins, lipids, and DNA. Many studies suggest that oxidative stress in patients with asthma is linked to increased consumption of antioxidants in the airways,19Kelly F.J. Vitamins and respiratory disease: antioxidant micronutrients in pulmonary health and disease.Proc Nutr Soc. 2005; 64: 510-526Crossref PubMed Scopus (31) Google Scholar as well as polymorphisms in genes encoding glutathione-S-transferase enzymes.20Yang I.A. Fong K.M. Zimmerman P.V. Holgate S.T. Holloway J.W. Genetic susceptibility to the respiratory effects of air pollution.Thorax. 2008; 63: 555-563Crossref PubMed Scopus (23) Google Scholar In a study of children with mild asthma, levels of the enzymes glutathione peroxidase and superoxide dismutase and of the nonenzymatic components of the antioxidant system were all found to be significantly lower in children with asthma compared with those seen in healthy control subjects.21Sackesen C. Ercan H. Dizdar E. Soyer O. Gumus P. Tosun B.N. et al.A comprehensive evaluation of the enzymatic and nonenzymatic antioxidant systems in childhood asthma.J Allergy Clin Immunol. 2008; 122: 78-85Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar A nitrotyrosine proteome survey in patients with asthma identified an oxidative mechanism of catalase inactivation, and analysis of bronchoalveolar lavage fluid revealed a 50% reduction in catalase activity relative to that seen in healthy control subjects.22Ghosh S. Janocha A.J. Aronica M.A. Swaidani S. Comhair S.A. Xu W. et al.Nitrotyrosine proteome survey in asthma identifies oxidative mechanism of catalase inactivation.J Immunol. 2006; 176: 5587-5597PubMed Google Scholar Most recently, children with severe asthma have been shown to have increased biomarkers of oxidant stress in the epithelial lining fluid.23Fitzpatrick A.M. Teague W.G. Holguin F. Yeh M. Brown L.A. Airway glutathione homeostasis is altered in children with severe asthma: evidence for oxidant stress.J Allergy Clin Immunol. 2009; 123: 146-152Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Furthermore, there is evidence that the epithelium is deficient in its ability to neutralize oxidant attack through a decrease in antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, in patients with asthma.24Comhair S.A. Xu W. Ghosh S. Thunnissen F.B. Almasan A. Calhoun W.J. et al.Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity.Am J Pathol. 2005; 166: 663-674Abstract Full Text Full Text PDF PubMed Google Scholar, 25Comhair S.A. Bhathena P.R. Farver C. Thunnissen F.B. Erzurum S.C. Extracellular glutathione peroxidase induction in asthmatic lungs: evidence for redox regulation of expression in human airway epithelial cells.FASEB J. 2001; 15: 70-78Crossref PubMed Scopus (98) Google Scholar Levels of vitamin C and E are also low in patients with mild asthma,26Kelly F.J. Mudway I. Blomberg A. Frew A. Sandstrom T. Altered lung antioxidant status in patients with mild asthma.Lancet. 1999; 354: 482-483Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar although longitudinal studies suggest that antioxidant supplementation during adulthood is not an important determinant of asthma, and only vitamin E has a modest protective effect.27Troisi R.J. Willett W.C. Weiss S.T. Trichopoulos D. Rosner B. Speizer F.E. A prospective study of diet and adult-onset asthma.Am J Respir Crit Care Med. 1995; 151: 1401-1408Crossref PubMed Google ScholarIn addition to inhaled and endogenously produced oxidants, epidemiologic studies show that regular exposure to paracetamol (acetaminophen) in the interuterine environment28Shaheen S.O. Newson R.B. Sherriff A. Henderson A.J. Heron J.E. Burney P.G. et al.Paracetamol use in pregnancy and wheezing in early childhood.Thorax. 2002; 57: 958-963Crossref PubMed Scopus (118) Google Scholar in children28Shaheen S.O. Newson R.B. Sherriff A. Henderson A.J. Heron J.E. Burney P.G. et al.Paracetamol use in pregnancy and wheezing in early childhood.Thorax. 2002; 57: 958-963Crossref PubMed Scopus (118) Google Scholar, 29Beasley R. Clayton T. Crane J. von M.E. Lai C.K. Montefort S. et al.Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6-7 years: analysis from Phase Three of the ISAAC programme.Lancet. 2008; 372: 1039-1048Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar and in adults30Nuttall S.L. Williams J. Kendall M.J. Does paracetamol cause asthma?.J Clin Pharm Ther. 2003; 28: 251-257Crossref PubMed Scopus (20) Google Scholar carries a dose-dependent risk of allergy and asthma. Several biologic mechanisms have been proposed to explain the association between paracetamol consumption and asthma, including glutathione depletion caused by metabolism of the drug. This depletion is proposed to increase the risk of lung tissue damage and ultimately of respiratory disease.30Nuttall S.L. Williams J. Kendall M.J. Does paracetamol cause asthma?.J Clin Pharm Ther. 2003; 28: 251-257Crossref PubMed Scopus (20) Google Scholar Other mechanisms that might link paracetamol to the development of asthma include enhanced production of prostaglandin E2 to promote TH2 allergic pathways or an IgE-mediated mechanism with acetaminophen as the antigenic agent.31Allmers H. Frequent acetaminophen use and allergic diseases: is the association clear?.J Allergy Clin Immunol. 2005; 116: 859-862Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Based on current knowledge, further research into the effects of paracetamol on the incidence of childhood asthma is urgently needed to enable guidelines for the recommended use of paracetamol in childhood to be made.Our current understanding of the role of oxidative stress in asthma suggests that antioxidant therapy to improve the chemical barrier might be important in optimizing asthma treatment and prevention; however, previous trials with conventional antioxidant therapy in patients with asthma have been largely ineffective. This might be due to the need to select appropriate target populations and strategies that have broad effects on the antioxidant balance.32Riedl M.A. Nel A.E. Importance of oxidative stress in the pathogenesis and treatment of asthma.Curr Opin Allergy Clin Immunol. 2008; 8: 49-56Crossref PubMed Scopus (82) Google Scholar However, although restoration of antioxidant defense might be beneficial, this defense system is only one facet of the epithelial barrier that is abnormal in patients with asthma. Thus fixing this aspect alone might not be an effective treatment strategy.The physical barrier of the airwaysThe mucociliary escalatorThe bronchial secretions, with their gel-like properties, play an important role in forming a physical barrier to the environment. The properties of the mucus are dictated in large part by the oligomeric secreted mucins MUC5AC and MUC5B.14Thornton D.J. Rousseau K. McGuckin M.A. Structure and function of the polymeric mucins in airways mucus.Annu Rev Physiol. 2008; 70: 459-486Crossref PubMed Scopus (169) Google Scholar These multifunctional glycoproteins provide the structural framework of the mucus barrier and serve to trap inhaled particles, which are then moved out of the airways through the action of the mucociliary escalator. The importance of mucins for host defense has been illustrated in models of colitis, in which Muc2 deficiency leads to inflammation of the colon and contributes to the onset and perpetuation of experimental colitis.33Van der S.M. De Koning B.A. De Bruijn A.C. Velcich A. Meijerink J.P. Van Goudoever J.B. et al.Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection.Gastroenterology. 2006; 131: 117-129Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar Mucins are produced throughout the bronchial tree, particularly by goblet cells and mucus and serous cells of the submucosal glands.14Thornton D.J. Rousseau K. McGuckin M.A. Structure and function of the polymeric mucins in airways mucus.Annu Rev Physiol. 2008; 70: 459-486Crossref PubMed Scopus (169) Google Scholar In patients with asthma, there is evidence of abnormal mucin production, as demonstrated by an increased number of goblet cells34Ordonez C.L. Khashayar R. Wong H.H. Ferrando R. Wu R. Hyde D.M. et al.Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression.Am J Respir Crit Care Med. 2001; 163: 517-523Crossref PubMed Google Scholar and increased amounts of polymeric mucins compared with levels seen in normal induced sputum,35Kirkham S. Sheehan J.K. Knight D. Richardson P.S. Thornton D.J. Heterogeneity of airways mucus: variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B.Biochem J. 2002; 361: 537-546Crossref PubMed Scopus (126) Google Scholar which might contribute to mucus plugging of the airways. Other factors that contribute to mucus plugging include DNA, serum proteins, and eosinophilic basic proteins. However, in a trial with the mucolytic drug recombinant human deoxyribonuclease as an add-on to standard treatment, there was no beneficial effect in children presenting to the emergency department with acute asthma exacerbations.36Boogaard R. Smit F. Schornagel R. Vaessen-Verberne A.A. Kouwenberg J.M. Hekkelaan M. et al.Recombinant human deoxyribonuclease for the treatment of acute asthma in children.Thorax. 2008; 63: 141-146Crossref PubMed Scopus (12) Google ScholarEpithelial tight junctionsIn addition to the secretory mucus, the epithelial cells lining the airway elaborate a selective physical barrier between the external environment and the internal tissues (Fig 1).37Ikenouchi J. Sasaki H. Tsukita S. Furuse M. Tsukita S. Loss of occludin affects tricellular localization of tricellulin.Mol Biol Cell. 2008; 19: 4687-4693Crossref PubMed Scopus (52) Google Scholar, 38Gonzalez-Mariscal L. Betanzos A. V