Development of new therapy for airway goblet cell metaplasia by transition to ciliated cells

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1. In vitro study using highly differentiated epithelial cell culture. Interleukin (IL)-13 induces goblet cell metaplasia and plays an important role in mucus hypersecretion in asthma. In this study, we asked whether elimination of IL-13 could reverse the established goblet cell metaplasia into ciliated epithelia. Primary epithelial cells from guinea pig tracheas were cultured at an air-liquid interface with the medium containing human recombinant IL-13 for 14 days, and continuously cultured with IL-13-eliminated medium, or cultured under the condition of neutralization of IL-13 with anti IL-13 antibody. After 2 days from elimination of IL-13, PAS-positive area as well as MUC5AC protein level rapidly decreased. After 4 days, the number of goblet cells dramatically decreased, while that of ciliated cells inversely increased. Total number of epithelial cells did not change, and 5-bromo-2'-deoxyuridine uptake decreased after IL-13 elimination. Transitional cells with cilia and secretory granules increased after IL-13 elimination. Similarly, the neutralization of IL-13 with anti IL-13 antibody for 5 days reversed the goblet cell metaplasia into ciliated epithelia, and transitional cells also increased.2. In vivo study using remodeled airway in sensitized guinea pigs. Airway goblet cell metaplasia was obtained by repeated ovalbumin sensitization in guinea pigs, and the effects of Th2 inhibitor, anti IL-13 antibody and steroid on goblet cell metaplasia were investigated.,Tracheas were removed and stained with PAS/alcian blue. Mucus area was assessed by computer image analysis. As a result, mucus area was suppressed by the inhibitors, and transitional cells with both cilia and mucus granules appeared.3. Anti IL-13 therapy may reverse goblet cell metaplasia into ciliated epithelia. Transition of goblet cells to ciliated cells is provably involved in this phenomenon. Anti IL-13 therapy may be a therapeutic strategy of established goblet cell metaplasia in asthma.