Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease

Abstract

Mucous cell metaplasia is induced in response to harmful insults and provides front-line protection to clear the airway of toxic substances and cellular debris. In chronic airway diseases mucous metaplasia persists and results in airway obstruction and contributes significantly to morbidity and mortality. Mucus hypersecretion involves increased expression of mucin genes, and increased mucin production and release. The past decade has seen significant advances in our understanding of the molecular mechanisms by which these events occur. Inflammation stimulates epidermal growth factor receptor activation and IL-13 to induce both Clara and ciliated cells to transition into goblet cells through the coordinated actions of FoxA2, TTF-1, SPDEF, and GABA(A)R. Ultimately, these steps lead to up-regulation of MUC5AC expression, and increased mucin in goblet cell granules that fuse to the plasma membrane through actions of MARCKS, SNAREs, and Munc proteins. Blockade of mucus in exacerbations of asthma and chronic obstructive pulmonary disease may affect morbidity. Development of new therapies to target mucus production and secretion are now possible given the advances in our understanding of molecular mechanisms of mucous metaplasia. We now have a greater incentive to focus on inhibition of mucus as a therapy for chronic airway diseases.

Figure 1.

Apical surface of a goblet cell releasing mucin. Electron micrograph of a murine goblet cell. A mucin-containing vesicle has fused to the plasma membrane of the apical airway surface. Note the electron-dense, dark granules that become flocculent and less dense as mucin extrusion occurs and the mucin becomes hydrated. Cross-sections of cilia in the airway lumen are from adjacent ciliated cells.

Figure 2.

Goblet cell differentiation requires two signals. The hypothesis: Signal 1 activates the epidermal growth factor receptor (EGFR) on the ciliated cells, leading to inhibition of epithelial cell apoptosis. Epithelial cells that survive have the potential to become goblet cells if provided with Signal 2, IL-13 binding to its receptor. Upon IL-13R and Stat6 activation, epithelial cells show an increase in SPDEF and reduced FoxA2 expression. These effects are IL-13 dependent, yet their blockade inhibits goblet cell induction, placing them early in goblet cell transition. GABAA-R responsiveness is required for goblet cell metaplasia and is induced by IL-13. After IL-13 activation, cells lose the features of epithelial cells from which they arose and become goblet cells that produce mucins and other factors necessary for secretory functions.