From Mucins to Mucus
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Mucus is essential for protection of the airways; however, in chronic airway disease mucus hypersecretion is an important factor in morbidity and mortality. The properties of the mucus gel are dictated in large part by the oligomeric mucins and, over the past decade, we have gained a better understanding of the molecular nature of these complex O-linked glycoproteins. We know now that MUC5AC mucins, as well as different glycoforms of the MUC5B mucin, are the predominant gel-forming glycoproteins in airways mucus. Furthermore, the amount, molecular size, and morphology of these glycoproteins can be altered in disease. From more recent data, it has become clear that oligomeric mucins alone do not constitute mucus, and other mucin and nonmucin components must be important contributors to mucus organization and hence airways defense. Therefore, the challenge over the coming decade will be to investigate how the oligomeric mucins are organized to yield “functional” mucus. Such studies will provide a clearer pe...Cite
Patients with coronavirus disease 2019 (COVID-19) exhibit a spectrum of respiratory symptoms like cough and dyspnea.1-3 Airway mucus is an adhesive viscoelastic gel composed mostly of high-molecular-weight mucous glycoproteins and water, which is important in maintaining lung function and health, pathological mucus hypersecretion may cause airway obstruction and lead to respiratory distress. Mucin (MUC) glycoproteins are the major macromolecular components of mucus, which are classified into two major types: the gel-forming secreted MUC5AC and the membrane-tethered MUC1.4 Here, with an attempt to understand the lung changes, we sought to provide a delineation of the components of airway mucus from patients with COVID-19. To clean airway obstruction, respiratory tract mucus was aspirated and collected via bronchoscopy from COVID-19 patients with a critical illness, and optical coherence tomography (OCT) was applied via bronchoscopy to obtain cross-sectional images of the bronchiole. For healthy control, sputum was induced by inhaled hypertonic (3%) saline solution delivered with an ultrasonic nebulizer. After collection, sputum was processed as previously described for components analysis.5 Medical history, and clinical and laboratory data of the participants were extracted from electronic medical records. The study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (No. 2020-65). The requirement for informed consent was waived because the study was observational and the family members were in quarantine. MUC5AC (sc-21701; Santa Cruz, Shanghai, China) and MUC1 (sc-6827; Santa Cruz) in airway mucus were measured using enzyme-linked immunosorbent assay, and MUC1-cytoplasmic tail (CT, clone EP1024Y; Abcam, Shanghai) levels were measured by Western blot analysis as described previously.5 The levels of MUC5AC and MUC1 were normalized to their average signal reading of a healthy control group. A total of 16 patients with COVID-19 were included in this study, the clinical characteristics of the recruited subjects were shown in Table S1. There was no significant deviation in the distribution of age, or sex between the cohorts of case and control subjects. All the patients with COVID-19 were admitted to the intensive care unit because of low oxygenation index (199 ± 23 mm Hg), and 79% of them received mechanical ventilation. Blood laboratory tests showed elevated inflammatory indexes including leukocyte count, C-reactive protein, and interleukin-6 in most of the patients with COVID-19 (Table S2). OCT indicated clear bronchiole in healthy controls (Figure 1A) and mucus retention in the bronchiole of patients with COVID-19 (Figure 1B). A volume of 1-8 mL white to gray sputum with high viscosity (Figure 1C) was aspirated from the respiratory tract of 16 patients with COVID-19. Induced sputum from healthy control was clear and transparent with low viscosity. Compared to healthy control, airway mucus from patients with COVID-19 had a higher level of MUC5AC (Figure 1D), MUC1 (Figure 1E), and MUC1-CT fragment (Figure 1F). However, there were no significant differences in the concentration of total protein, sodium, or chloride in the airway mucus from patients with COVID-19 when compared to healthy control (Table S3). Although more than half of patients with COVID-19 presented with a dry cough,6 this study provided direct evidence showing mucus retention in the small airway of patients with COVID-19, and patients were not able to expectorate by themselves and need bronchoscopy aspiration to help them to clean respiratory tract. The sputum from these patients with COVID-19 was viscous, which is not surprising as MUC5AC levels are extremely high, hyperconcentration of this gel-forming MUC dehydrates airway surfaces and causes mucus adhesion, which may contribute to airflow obstruction and respiratory distress. Clearance of airway mucus is an important way to increase oxygen and carbon dioxide exchange, bronchoscopy aspiration of airway mucus was used in all our patients to relieve hypoxia. In our center, all the 16 critical ill COVID-19 patients recovered and were discharged from hospitalization, which may attribute to our aggressive clearance of the respiratory tract. It is of note that bedside bronchoscopy may not be available in some hospitals as the medical resources are limited during the COVID-19 pandemic, carbocisteine has been reported to inhibit airway MUC5AC secretion, which could be used to reduce sputum viscosity and elasticity in patients with COVID-19. In addition, hydration of sputum by aerosolized hypertonic saline solutions or mannitol, and dilation of bronchi via aerosolized salbutamol may facilitate sputum expectoration. MUC1 is a membrane-tethered MUC expressed on the apical surface of epithelial cells.7, 8 Since MUC1-CT fragment is on the cytoplasmic side of the cells, the elevated sputum CT fragment in patients with COVID-19 could come from detached and disrupted epithelial cells, which is evidenced by the pathological findings of diffuse alveolar damage with fibromyxoid exudates and macrophage infiltration in the lung tissue from patients with COVID-19.9 The limitation of this study is that induced sputum was used in the control group to compare airway mucus aspirated via bronchoscopy from patients with COVID-19, because it was very difficult for the patients with COVID-19 to expectorate sputum even with hypertonic saline solution inhalation. The findings may suggest that increased level of MUCs in the airway mucus may contribute to the high viscosity of airway mucus and sputum retention in the small airway of patients with COVID-19, airway mucus clearance may be indicated to relieve respiratory distress, and MUC5AC may serve as a target for mucolytic agents in treating COVID-19. And MUC1-CT may serve as an indicator reflecting the severity of airway and alveolar epithelial cell damage. This study was supported by grants from the National Key R&D Project (2016YFC0903700 and 2016YFC1304102), the National Natural Science Foundation of China (81520108001 and 81770043), and grant specific for COVID-19 study from Guangzhou Institute of Respiratory Health. The authors would like to thank Dr Kwang Chul Kim (University of Arizona) for the invaluable assistance with the manuscript. The authors declare that there are no conflict of interests. NZ, YL, WL, and JZ conceived and designed the experiments. TW and WL analyzed the data and wrote the manuscript. XL, FY, and JH collected the samples and clinical data. FL, AZ, YL, and JL performed the experiments. All authors have read and approved the final manuscript. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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2019-20 coronavirus outbreak
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The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103(+) type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
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The mucus layer that coats the airway epithelium provides a protective barrier against pathogenic and noxious agents and participates in the mucosal response to inflammation and infection. Airway mucus is composed of water, ions, lung secretions, serum protein transudates, and mucin glycoproteins (mucins). Mucins are the major components of mucus and the macromolecules that impart rheologic properties to airway mucus (1, 2). Airway mucus is overproduced in the upper and/or lower respiratory tracts during acute challenges and in chronic conditions (asthma, cystic fibrosis, bronchitis, and sinusitis), thereby contributing to mucus obstruction of the airways (3). Mucus obstruction is the culmination of several complex processes including mucin ( MUC ) gene regulation, mucin secretion and goblet cell hyperplasia (GCH) (Figure 1). Insight into each of these processes is limited; more detailed information about fundamental cellular mechanisms will be required to better understand their interrelationships. For example, pathogenic agents and inflammatory mediators initiate secretion of mucins (4–7) and sustain mucin production by increasing expression of mucin genes (8, 9). Nevertheless, each process has markedly different kinetics and their response to mediators likely involves different cellular signaling and pathways. The increasing availability of molecular probes for specific mucin genes and gene products is beginning to provide some insights into the pathogenesis of mucus overproduction. However, detailed information about the expression and regulation of respiratory tract mucins in specific disease entities is still incomplete. The report by Chen and colleagues (10) provides new information on altered expression of a specific mucin gene, MUC5B.
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Submucosal glands
Mucociliary clearance
Airway obstruction
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The epithelium of the respiratory mucosa provides a barrier against injurious luminal agents, including bacteria, enzymes, and toxins. The normal respiratory epithelium is coated with mucus, which provides a variety of protective functions, including protection of the lower airways from dehydration and from damaging airborne irritants, particles, and microorganisms. The adhesive and viscoelastic properties of mucus glycoproteins (mucins), the major protein components of airway mucus, allow the trapping of foreign substances and their transport and removal on the tips of beating cilia toward the throat, a process termed mucociliary clearance. However, overzealous production of mucus may significantly contribute to the morbidity and mortality associated with certain respiratory diseases. In particular, mucus hypersecretion and plugging of the airways are characteristic features of patients who die from asthma (1, 2), chronic bronchitis, and cystic fibrosis (2). In human airways, mucins are produced and secreted by specialized cells in the epithelium, including the goblet cells in the surface airway epithelium and the secretory (mucous and serous) cells in the submucosal glands. Because of their greater prominence in histologic sections, submucosal glands, rather than goblet cells, have been thought to contribute the greater quantity of mucus to airway surface fluid (3). However, recent studies suggest that goblet cells may contribute more to the overall quantity of mucus produced than do the submucosal glands. Mucins constitute a heterogeneous group of high molecular weight, richly glycosylated molecules. To date, nine human mucin genes ( MUC1 , MUC2 , MUC3 , MUC4 , MUC5/5AC , MUC5B , MUC6 , MUC7 , and MUC8 ) encoding the protein core of mucin have been identified (reviewed in Reference 4). The biologic importance of these diverse mucin proteins is not currently known. Nonetheless, there appears to be some degree of specificity in the tissue expression of the various MUC genes. In the respiratory tract, seven of the nine MUC genes are expressed ( MUC1 , MUC5/5AC , MUC2 , MUC4 , MUC5B , MUC7 , and MUC8 ) (reviewed in Reference 4). The mechanisms governing mucin glycoprotein synthesis and secretion are not well understood in either health or disease. Control of mucus secretion is a complex process involving regulation at many different levels, including ( 1 ) cell proliferation and differentiation, ( 2 ) mucin gene expression, and ( 3 ) release of mature mucin molecules from storage granules (3). Under normal conditions, there are relatively few goblet cells in the human airway and virtually none in the airways of animals kept in clean environments. In response to a wide variety of stimuli, including proteinases, irritant gases, inflammatory mediators, reactive oxygen species, and cholinergic and nonadrenergic, noncholinergic nerve activation, a rapid increase in the number of airway goblet cells is observed via both hyperplastic (cell division) and metaplastic (cell differentiation) mechanisms. In the airways of rodents, these increases are primarily due to metaplasia, since goblet cells are not normally seen in the airways of clean animals. Secondly, MUC gene transcription has been shown to be induced upon exposure of the airways to a number of substances that induce mucus secretion, such as endotoxin, SO 2 , and allergens (5, 6). Thus, it is hypothesized that an important point of control of mucus secretion is the synthesis of these protein backbones of the mature mucin glycoproteins. Although the exact molecular mechanisms regulating mucin-gene expression are virtually unknown, there is evidence that the individual genes may be differentially regulated. For example, Muc-2 expression is induced in the lungs of rats exposed to SO 2 and Sendai virus, but not by allergen exposure (5, 6). Conversely, allergen challenge has been shown to induce MUC5 gene expression (6). Lastly, secretion of mature mucin molecules requires their release from the intracellular granules in which they are stored. To date, there are a number of inflammatory mediators implicated in the allergic diathesis that are known to influence goblet-cell secretion, including the prostaglandins E2 and F2a, leukotrienes, 15-HETES, platelet-activating factor, mast-cell and neutrophil proteases, eosinophil cationic protein, and the cytokines interleukin (IL)-1 and tumor necrosis factor (TNF) (3). As stated above, mucus hypersecretion is a key feature of allergic asthma and is associated with the clinical symptoms, airway obstruction, and mortality of the disease. Because of the difficulty of studying molecular processes in the human lung, much of our current knowledge of mucus regulation has come from the study of murine models of allergic disease. Recently, several groups of investigators have shown that respiratory challenge with allergens causes physiologic and pathologic changes similar to those seen in human allergic asthma, including airway hyperresponsiveness, airway inflammation, and airway goblet-cell metaplasia (GCM), as evidenced by periodic acid-Schiff (PAS) ( Received in original form May 3, 2000 )
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Mucus plays a vital role in protecting the lungs from environmental factors, but conversely, in muco-obstructive airway disease, mucus becomes pathologic. In its protective role, mucus entraps microbes and particles removing them from the lungs via the co-ordinated beating of motile cilia. This mechanism of lung defence is reliant upon a flowing mucus gel, and the major macromolecular components that determine the rheological properties of mucus are the polymeric mucins, MUC5AC and MUC5B. These large O-linked glycoproteins have direct roles in maintaining lung homeostasis. MUC5B is essential for interaction with the ciliary clearance system and MUC5AC is up-regulated in response to allergic inflammatory challenge. Mucus with abnormal biophysical properties is a feature of muco-obstructive respiratory disease and can result from many different mechanisms including alterations in mucin polymer assembly, mucin concentration and the macromolecular form in mucus, as well as changes in airway surface hydration, pH and ion composition. The abnormal mucus results in defective lung protection via compromised ciliary clearance, leading to infection and inflammation.
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Many of the proteins associated with innate immunity in the upper respiratory tract are to be found localized into mucus gels and the mucin-rich surface layers of the epithelium and the cilia. Mucus is a relatively dilute suspension of such macromolecules being around 2-4% solids in normal induced sputum. These proteins scavenge, immobilise and/or kill pathogens and at the same time immobilize them into the mucus. Mucus is moved from the lung by the mucociliary clearance mechanisms or by cough. Some 190 proteins are readily detectable in sputum by proteomics methods and about 100 in bronchial air-liquid interface culture secretions. This cell culture system mimics the surface ciliated phenotype of the large airways very well and about 85 secreted proteins are common to both culture and sputum secretions. The major single protein by weight in cell culture secretions is MUC5B and in sputum a mixture of MUC5B and MUC5AC. The three epithelial mucins MUC1, 4 and 16 are also detectable in both secretions. In this paper the roles that these molecules play in protecting and stabilising the ciliated surface and building the gel will be discussed. The role of water and ion homeostasis is particularly crucial in mucus gel formation and evidence is gathering that it is perturbation of hydration mechanisms that may play into defective mucus leading subsequently to stasis and mechanical problems.
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Respiratory tract
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