MUC5B is the principal secreted airway mucin, present in airway mucus at a concentration z10-fold higher than the other secreted airway mucin, MUC5AC (1, 2). The report in 2011 that a polymorphism upstream of the MUC5B gene is a risk factor for idiopathic pulmonary fibrosis (IPF) was surprising and illuminating for several reasons (3). First, a rare disease was found to be associated with a common allele (present in 20% of Caucasians), suggesting that genetic susceptibility might be a major contributor to disease pathogenesis even in sporadic IPF. Second, a disease that centers morphologically on the alveolar region of the lung appeared to be associated with an allele of a gene expressed in the conducting airways. Third, the mutation was found to cause a gain of function resulting in increased MUC5B expression. Since Muc5b is the mucin that is primarily responsible for particle clearance in the airways of mice (4), a loss of function could have been expected to result in interstitial lung disease simply by reducing clearance of inhaled particles. This possibility was particularly appealing because there is a dose dependency of mucociliary clearance on Muc5b expression, with a 50% reduction in expression resulting in a 50% reduction in clearance, and a progressive loss of expression with aging in mice (5). A loss-offunction mutation would have placed IPF on a continuum with pneumoconioses, in which the inhalation of large amounts of inorganic particles overwhelms normal clearance mechanisms, with both disorders resulting from an imbalance between particle exposure and clearance. However, the polymorphism associated with IPF results in 10-to 20-fold overexpression of MUC5B (3).

Further discoveries from a variety of sources have extended the implications of MUC5B’s association with IPF. Multiple additional IPF susceptibility genes have been identified, and the most common are those involved in telomerase maintenance, together accounting for z30% of the risk for IPF (6, 7). Their involvement suggests that a key pathway in IPF pathogenesis is lung epithelial progenitor cell depletion. Recent work using virus injury models indicates that alveolar regions can be repopulated by the migration of epithelial progenitors from distal conducting airways (8–10). The abundance of goblet, basal, and ciliated cells (normally characteristic of conducting airway epithelium) in remodeled lung parenchyma in IPF (11, 12) is consistent with this notion, bringing us back to the airway protein MUC5B.