Mucins: the frontline defence of the lung

Abstract

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.

Keywords: molecular basis of health and disease; mucin; mucus; respiratory physiology.

Figure 1.. Schematic representation of the domain structure of the polymeric mucins MUC5AC and MUC5B.

MUC5AC and MUC5B consist of vWF-like D domains (red) in the order D1–D2–D′–D3 at the N-terminus. The domains at the C-terminus are in the order D4–B–C–CK. The central mucin domain is composed of repetitive (grey) and non-repetitive sequences (green) enriched in serine, threonine and proline, interspersed with a variable number of Cys domains (blue); nine for MUC5AC and seven for MUC5B. The D3 and CK domains are the sites of intermolecular disulfide linkage that form the mucin polymers.

Figure 2.. Lung mucins in health and disease.

(A) In healthy airways, the protective mucus barrier consists mainly of MUC5B (blue) with a lesser amount of MUC5AC (red) that entraps inhaled particles and microbes. MUC5B bundles are shown emanating from submucosal glands. Optimal airway hydration maintains the correct rheological properties of the mucus gel, permitting efficient MCC. (B) In obstructive airway disease, mucin concentration is increased, which collapses the PCL, compresses cilia and impairs or stops MCC.