Mucous hypersecretion is a major cause of airway obstruction in asthma, chronic obstructive pulmonary disease, and cystic fibrosis. EGFR ligands and IL-13 are known to stimulate mucous induction, but the detailed mechanisms of epithelial mucous regulation have not been well defined. In this issue of the JCI, Tyner et al. show, in a mouse model of chronic mucous hypersecretion, that ciliated epithelial cell apoptosis is inhibited by EGFR activation, allowing IL-13 to stimulate the differentiation of these cells into goblet cells, which secrete mucus. In defining this coordinated, 2-step process, we can consider the therapeutic effects of blocking mucous production. This begs the question, Is it possible to reduce airway obstruction in chronic lung disease by inhibiting EGFR activation and/or by inhibiting IL-13?

In the respiratory tract, mucus is a critical component of the innate host defense system. On the airway epithelial cell surface, the sticky gel layer traps particles and the sol layer, which is predominantly water, contacts the surface of ciliated cells and permits moving of the gel out of the lower airways like an escalator so that it can ultimately be cleared by coughing or swallowing. Mucus also contains antibacterial agents to aid in its defense function. Pathogens and harmless proteins we inhale are thus removed from the respiratory tract and have a limited encounter with other immune components. In the bronchial airways, mucus is produced by surface epithelial cells with secretory features and a classical goblet shape, called goblet cells. Goblet cells produce mucins that are complexed with water in secretory granules and are released into the airway lumen. In the large airways, mucus is also produced by mucous glands. Under basal conditions, the columnar epithelial surface comprises a small percentage of goblet cells and a majority of ciliated cells. This structure provides adequate mucus to capture particles and remove them in the huge volumes of air we breathe. After infection or toxic exposure, the airway epithelium upregulates its mucous secretory ability, and we cough and bring up sputum. Subsequently, the airway epithelium recovers and returns to its normal state, goblet cells disappear, and coughing abates.