Mucins in airway secretions from healthy and chronic bronchitic subjects

Davies, Julia R.; Hovenberg, Hans W.; Lindén, Carl-Johan; Howard, Richard; Richardson, P. S.; Sheehan, John K.; Carlstedt, Ingemar

doi:10.1042/bj3130431

Cited by 56 publications

(39 citation statements)

References 32 publications

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“…Moreover, the lowercharged glycoform of MUC5B is increased in the COPD sputum. This is in agreement with previous analyses of MUC5B isolated from COPD sputum, which demonstrated a decrease in ''acidity'' of the mucin compared with that from normal subjects (11,20). Whether this is due to a gross change in glycosylation machinery of MUC5B-secreting cells or production from a specific population of MUC5B-secreting cells is not currently known.…”

Section: Discussionsupporting

confidence: 80%

“…In this regard, mucus plugging the airways of an individual in status asthmaticus was enriched in the low-charged form of MUC5B (22). Altered glycosylation of mucins has previously been reported in airways disease (11,20,23). Because mucin glycans are known receptors for microorganisms, changes in glycosylation might favor bacterial colonization, increasing the risk of exacerbation and infection (24,25).…”

Section: Discussionmentioning

confidence: 98%

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MUC5B Is the Major Mucin in the Gel Phase of Sputum in Chronic Obstructive Pulmonary Disease

Kirkham

Kolsum²,

Rousseau³

et al. 2008

Am J Respir Crit Care Med

125

127

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Rationale: Overproduction of mucus is a contributory factor in the progression of chronic obstructive pulmonary disease (COPD). The polymeric mucins are major macromolecules in the secretion. Therefore, we hypothesized that the polymeric mucin composition or properties may be different in the sputum from individuals with COPD and smokers without airflow obstruction. Objectives: To determine the major polymeric mucins in COPD sputum and whether these are different in the sputum from individuals with COPD compared with that from smokers without airflow obstruction. Methods: The polymeric mucin composition of sputum from patients with COPD and smokers without airflow obstruction was analyzed by Western blotting analysis. The tissue localization of the mucins was determined by immunohistochemistry, and their size distribution was analyzed by rate-zonal centrifugation. Measurements and Main Results: MUC5AC and MUC5B were the major mucins. MUC5AC was the predominant mucin in the smoker group, whereas MUC5B was more abundant from the patients with COPD, with a significant difference in the ratio of MUC5B to MUC5AC (P 5 0.004); this ratio was correlated with FEV 1 in the COPD group (r 5 0.63; P 5 0.01). The lower-charged glycosylated form of MUC5B was more predominant in COPD (P 5 0.012). No significant associations were observed with respect to sex, age, or pack-year history. In both groups, MUC5AC was produced by surface epithelial cells and MUC5B by submucosal gland cells. Finally, there was a shift toward smaller mucins in the COPD group. Conclusions: Our data indicate that there are differences in mucin amounts and properties between smokers with and without COPD. Further studies are needed to examine how this may impact disease progression.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 98%

MUC5B Is the Major Mucin in the Gel Phase of Sputum in Chronic Obstructive Pulmonary Disease

Kirkham

Kolsum²,

Rousseau³

et al. 2008

Am J Respir Crit Care Med

125

127

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“…Airway mucins from chronic bronchitis patients overall are similar in size and structure to mucus from healthy individuals, but appear to be less acidic (56). However, glycosylation patterns vary during acute exacerbations, as chronic bronchitis mucins are highly sialylated with increased sialylated and sulfated Le x structures (147).…”

Section: Mucin Changes In Vivomentioning

confidence: 99%

Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

Rose

Voynow²

2006

Physiological Reviews

931

892

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This review focuses on the role and regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (≥50% carbohydrate, wt/wt). MUC protein backbones are characterized by numerous tandem repeats that contain proline and are high in serine and/or threonine residues, the sites of O-glycosylation. Secretory and membrane-tethered mucins contribute to mucociliary defense, an innate immune defense system that protects the airways against pathogens and environmental toxins. Inflammatory/immune response mediators and the overproduction of mucus characterize chronic airway diseases: asthma, chronic obstructive pulmonary diseases (COPD), or cystic fibrosis (CF). Specific inflammatory/immune response mediators can activate mucin gene regulation and airway remodeling, including goblet cell hyperplasia (GCH). These processes sustain airway mucin overproduction and contribute to airway obstruction by mucus and therefore to the high morbidity and mortality associated with these diseases. Importantly, mucin overproduction and GCH, although linked, are not synonymous and may follow from different signaling and gene regulatory pathways. In section i, structure, expression, and localization of the 18 human MUC genes and MUC gene products having tandem repeat domains and the specificity and application of MUC-specific antibodies that identify mucin gene products in airway tissues, cells, and secretions are overviewed. Mucin overproduction in chronic airway diseases and secretory cell metaplasia in animal model systems are reviewed in section ii and addressed in disease-specific subsections on asthma, COPD, and CF. Information on regulation of mucin genes by inflammatory/immune response mediators is summarized in section iii. In section iv, deficiencies in understanding the functional roles of mucins at the molecular level are identified as areas for further investigations that will impact on airway health and disease. The underlying premise is that understanding the pathways and processes that lead to mucus overproduction in specific airway diseases will allow circumvention or amelioration of these processes.

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“…In obstructive airway diseases such as fatal asthma (1), chronic obstructive pulmonary disease [COPD (2)], and cystic fibrosis (3), exaggerated airway epithelial mucin production leads to mucous plugging and ultimately to death. MUC5AC mucin contributes importantly to mucous plugging in these diseases (3)(4)(5)(6)(7). Multiple stimuli such as bacterial products (8,9), respiratory viruses (10), and cigarette smoke (11) induce mucin production via activation of an epidermal growth factor receptor (EGFR) cascade (12).…”

mentioning

confidence: 99%

CCL20/CCR6 Feedback Exaggerates Epidermal Growth Factor Receptor-Dependent MUC5AC Mucin Production in Human Airway Epithelial (NCI-H292) Cells

Kim

Lewis

Nadel

2011

The Journal of Immunology

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Mucous hypersecretion is an important feature of obstructive airway diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Multiple stimuli induce mucin production via activation of an epidermal growth factor receptor (EGFR) cascade, but the mechanisms that exaggerate mucin production in obstructive airway diseases remain unknown. In this study, we show that binding of CCL20, a G protein-coupled receptor (GPCR) ligand that is upregulated in the airways of subjects with obstructive airway diseases, to its unique GPCR CCR6 induces MUC5AC mucin production in human airway epithelial (NCI-H292) cells via metalloprotease TNF-α–converting enzyme (TACE)-dependent EGFR activation. We also show that EGFR activation by its potent ligand TGF-α induces reactivation of EGFR via binding of endogenously produced CCL20 to its receptor CCR6 in NCI-H292 cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating mucin production in the NCI-H292 cells. In NCI-H292 cells, TGF-α stimulation induced two phases of EGFR phosphorylation (EGFR-P). The second EGFR-P was TACE-dependent and was responsible for most of the total mucin induced by TGF-α. Binding of endogenously produced CCL20 to CCR6 increased the second EGFR-P and subsequent mucin production induced by TGF-α. In NHBE cells, TGF-α–induced EGFR activation did not lead to significant CCL20 production or to EGFR rephosphorylation, and less mucin was produced. We conclude that NCI-H292 cells but not NHBE cells produce CCL20 in response to EGFR activation, which leads to a second phase of EGFR-P and subsequent exaggerated mucin production. These findings have potentially important therapeutic implications in obstructive airway diseases.

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Mucins in airway secretions from healthy and chronic bronchitic subjects

Cited by 56 publications

References 32 publications

MUC5B Is the Major Mucin in the Gel Phase of Sputum in Chronic Obstructive Pulmonary Disease

MUC5B Is the Major Mucin in the Gel Phase of Sputum in Chronic Obstructive Pulmonary Disease

Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

CCL20/CCR6 Feedback Exaggerates Epidermal Growth Factor Receptor-Dependent MUC5AC Mucin Production in Human Airway Epithelial (NCI-H292) Cells

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