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?

IL-13 is a potent stimulator of mucus in vivo, and its effects extend beyond the classical Th2 lymphocyte response. After Sendai virus infection, mucous hyperproduction is driven by IL-13, and this occurs in the absence of a visible airway inflammatory response. Likewise, mucous production is IL-13 dependent in non–Th2 driven airway inflammation when IL-13 levels are very low in the airways (17). Furthermore, many cytokine-driven models of airway inflammation result in mucous hypersecretion, yet each has been shown to do this through the production of IL-13 (18). Other factors can also induce mucus. For example, LPS can stimulate low-level mucous production in IL-13–deficient mice (17), and many studies have shown a role for human neutrophil elastase in mucous production (19, 20). Even in light of the seminal studies of mucin gene expression by Carol Basbaum (21, 22), there is only a rudimentary understanding of how these mediators stimulate mucins, the contribution of different mucins to the protective response, and which pathways are active in human disease. IL-13 is likely to play a critical role in mucous induction in asthma, and it may prove to be an important stimulus for mucous production in other chronic airway diseases, despite their diverse inflammation profiles, as IL-13 levels in the respiratory tract are often elevated (23, 24). In addition to its role in mucin gene expression, IL-13 induces other components of the secretory machinery, further supporting its identification as a master regulator of the goblet cell (25). Other candidates for the second stimulus have not been studied in such depth. They are lined up, and it is hoped they will be tested in this model by the Tyner and Holtzman laboratory.

Inflammation in asthma results from an exuberant inflammatory response to allergens that pose no threat to the individual; therefore, reducing mucous production in response to these agents should improve patient symptoms. Blockade of mucus may be problematic if its overproduction facilitates removal of damaged cells. Inhaled steroids are effective in quelling both inflammation and mucous production in asthma, but even during this treatment, some inflammation persists, and when disease exacerbations occur, there is a swift increase in mucus. Clinical trials of inhibitors of IL-13, TGF-α, and EGFR offer potential solutions to control airway obstruction and are on the horizon. Blocking the production of mucus in COPD has more potential to be detrimental since normal mucus helps to eliminate bacteria from the airways. It is unknown whether the mucus in these distorted airways inhibits or even promotes bacterial growth. Given the high prevalence of COPD, it may be worth defining a balance point that separates effective and pathologic mucous production. Since inhaled steroids have limited effectiveness in chronic bronchitis, therapeutic targeting of IL-13, TGF-α, and EGFR offers a potential way to limit mucous production and improve lung function.