Airway mucus: the good, the bad, the sticky

Abstract

Mucus production is a primary defense mechanism for maintaining lung health. However, the overproduction of mucin (the chief glycoprotein component of mucus) is a common pathological feature in asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and lung cancer. Although it is associated with disease progression, effective therapies that directly target mucin overproduction and hypersecretion are lacking. Recent advances in our understanding of the control of mucin gene expression in the lungs, the cells that produce airway mucins, and the mechanisms used for releasing them into the airways have provided new potentials for the development of efficacious interventions that will be discussed in this review.

Figure 1.. Increased mucus production in allergically inflamed airways.

(Top) In healthy lungs, the airways are lined by a thin layer of mucus that is comprised of glandular and surface epithelial secretions. The mucus layer is present in airways from the level of the trachea to the bronchioles, and the steady state production and secretion of mucin are balanced. The mucus gel is thin, and mucous cells contain small amounts of histochemically detectable mucin. Throughout mouse airways and in bronchiolar human airways, gel-forming mucins are produced by Clara cells. (Bottom) In allergically inflamed airways, mucin production increases dramatically during a process called mucous cell metaplasia. This results in increased production of surface and glandular mucins in response to inflammatory cell products.

Figure 2.. Membrane associated and gel-forming mucins are secreted in the airways.

(Left) Membrane mucins present at the apical surfaces of airway epithelial cells participate in signal transduction directly (MUC1) and indirectly (MUC4). Gel-forming mucins are synthesized and packaged into secretory granules (SG’s) where they are positioned for rapid release in response to secretagogue stimulation. (Right) Membrane and gel-forming mucins can both be released into the airway mucus layer. Shear forces or enzymatic cleavage cause shedding of membrane mucins. Agonist stimulation causes SG release and gel-forming mucin secretion by regulated exocytosis. Gel-forming mucins are large branched polymers that contribute to the viscoelasticity of airway mucus.

Figure 3.. Gel-forming mucins are evolutionarily related to von Willebrand Factor and possess domain structures that are highly conserved.

(Top – human, Bottom – mouse) The N- termini of gel-forming mucins contain vWD domains, Cys-rich C8 domains, and the C-termini contain Cys-knot (CTCK) domains. These highly Cys-enriched regions contribute to mucin oligomerization by disulfide bonding. The central portions of gel-forming mucin apoprotiens are highly enriched in Pro (P), Thr (T), and Ser (S) amino acid residues in domains referred to as PTS-rich regions. In MUC2, the central PTS-rich region is a perfect repeat and is devoid of Ser residues. In MUC5AC/Muc5ac and MUC5B/Muc5b, the PTS-rich domain is an imperfect repeat that is interrupted by Cys-rich regions. MUC19/Muc19, Muc6, and MUC5AC/Muc5ac contain N-terminal trypsin inhibitor-like (TIL) domains.

Figure 4.. Gel-forming mucins are encoded at conserved chromosomal loci.

(Left) MUC 6, 2, 5AC, and 5B are encoded in the teleomeric region of the short arm of chromosome 11 (11p15.5), and their orthologs are encoded in the syntenic region of mouse chromosome 7 F5. MUC19 and Muc19 are encoded in conserved syntenic regions on human chromosome 12 and mouse chromosome 15.

Figure 5.. Signal transduction pathways and control of Muc5ac production.

Three pathways have been repeatedly shown to be critical for regulating MUC5AC/Muc5ac production. Conditional Foxa2 knockout mice develop spontaneous mucous metaplasia and Muc5ac overexpression. IL-13 and STAT6 are both necessary and sufficient for mucous metaplasia and Muc5ac induction during allergic inflammation. EGFR signaling is required as a parallel pathway for mucous metaplasia and MUC5AC/Muc5ac induction. A role for Wnt/β-catenin signaling is suggested by mouse transgenic models via down-regulation of Foxa2 by a yet undefined mechanism. Foxa2 acts as a repressor of MUC5AC/Muc5ac expression, but its action as a cis or trans acting repressor is unclear. HIF-1 is a cis acting activator of mouse Muc5ac promoter activity, and it may function as a central mediator of numerous inflammatory inputs.

Figure 6.. Mucin secretion by regulated exocytosis.

(1) Newly formed Mucin SG’s are transported to the apical region of the cell by microtubule based transport. (2) In the periphery SG’s transfer from microtubule to actin-myosin based transport. This is mediated by MARCKS, Rab27, Granulophilin, and atypical myosins. (3) Once localized at the plasma membrane, SG’s become loosely tethered (not shown) and then docked. Docking is mediated by the activities of Munc18 and Munc13 proteins, which bind to Syntaxin causing it to achieve an “open conformation” that allows it to bind to VAMP and SNAP-23. (4) Formation of this 4-helix coiled-coil complex is required for the last step of regulated exocytosis - fusion of SG’s with the plasma membrane. This step requires agonist driven activation of the Ca²⁺ sensor Synaptotagmin.

Figure 7.

Therapeutic strategies for blocking mucus hypersecretion.