Analysis of respiratory mucus glycoproteins in asthma: a detailed study from a patient who died in status asthmaticus.

Abstract

Airway mucus from asthmatics is often unusually solid. The death of a patient in status asthmaticus allowed the collection of 28 g of abnormal airway mucus at autopsy. Its chemical and physical properties were studied to reveal differences from more normal airway mucus. The gel plug taken from the airways could be dispersed in 6 M guanidinium chloride, but it took > 1 wk and 700 ml of extractant to disperse 3 g of exudate completely. In contrast, treatment with 10 mM dithiothreitol, which reduces disulfide bonds, dispersed the gel within seconds. Mucins accounted for 25% of the non-dialyzable material in the gel, while DNA constituted < 1% and proteoglycans could not be detected. The mucins were similar in architecture and general composition to other respiratory mucins and were present at a high concentration (approximately 40 mg/ml). The majority of mucins were of extreme size (mean M(r) 30-40 x 10(6)) and slow to dissolve, but sequential extraction experiments on the gel exudate demonstrated a proportion of mucins (15%), the most readily extracted, which had a higher density, 1.45-1.55 g/ml, a lower M(r) (11.5 x 10(6)) and were markedly more acidic than the bulk of the mucins. Both major and minor mucin populations were extremely heterogeneous in mass distribution. Electron microscopy of the major mucin species demonstrated extensive networks of molecules many microns in length. The major mucin species was distinctly less acidic than mucins previously described from either normal or diseased airways. Amino acid analysis of fractions across the charge distribution suggested the presence of at least two different mucin proteins occurring as distinct glycoforms.

Clinical relevance of airway remodelling in airway diseases

“…Impaired clearance of mucus is present during exacerbations of asthma [102] and is a particular feature of fatal asthma [19]. The rheological properties of mucus are altered in asthma [103,104] which may lead to reduced clearance and accumulation of mucus within the airways. Although increased luminal mucus is seen in post mortem cases of mild asthma [105] and is almost invariably a feature of cases of fatal asthma [99], increased mucus production is not a common clinical feature of mild-to-moderate asthma.…”

Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma

“…Many individuals with asthma, especially those with high levels of IL-13, have increased MUC5AC mRNA levels but decreased MUC5B mRNA levels (16). Increases in MUC5AC and MUC5B protein concentra tions have been reported in sputum from individuals with asthma (17) and in a mucus plug in an individual with fatal asthma (18). We sought to determine whether changes in mucus composition, organization, and function contribute to impaired mucus transport in asthma.…”

Allelic Association and Recombination Hotspots in the Mucin Gene (MUC) Complex on Chromosome 11p15.5

“…Reciprocally, in Crohn's disease MUC2 expression is decreased and an increase of MUC5AC and MUC6 expression is observed in the ileum (Buisine et al 2001). In respiratory disease both MUC5AC and MUC5B are upregulated (Copin et al 2000;Ordonez et al 2001;Sheehan et al 1995;Sheehan et al 1999). These genes each contain a large central exon, which encodes a domain of repeated sequences of non-identical serine and threonine rich units that forms the scaffold for the major O-glycosylation.…”