Barrier function of airway tract epithelium

Ganesan, Shyamala; Comstock, Adam T; Sajjan, Uma S

Goblet cell metaplasia and hyperplasia are also observed in patients with other chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and is induced by the coordinated action of EGFR and IL-13. 55-59 Downstream of IL-13, several transcription factors, e.g., thyroid transcription factor (TTF)-1, Sam pointed domain-containing ETS transcription factor (SPDEF), and forkhead transcription factor (FOX)A2, regulate goblet cell development downstream of IL-13. 60 While both TTF-1 and FOXA2 repress goblet cell metaplasia, 61,62 SPDEF promotes goblet cell metaplasia by downregulating FOXA2 and TTF-1. 62 Recently, increased SPDEF and decreased FOXA2 expression has been shown to contribute to the development of goblet cell hyperplasia in mouse models of asthma. [63] [64] [65] [66] SPDEF not only promotes goblet cell hyperplasia but also upregulates the network of genes associated with mucus production. 65 Inhibition of aldose reductase or SERPINb3a, both of which are induced in asthma reduced SPDEF expression, attenuates development of goblet cell hyperplasia. 63, 64 Additionally, TTF-1 was significantly reduced in patients with asthma and mice deficient in TTF-1 were found to be prone to develop goblet cell metaplasia upon exposure to allergens. 62 Therefore, strategies to modulate activities of TTF-1, FOXA2 or SPDEF may attenuate goblet cell metaplasia and mucus production, thus improving mucociliary function in patients with asthma and other chronic airway diseases.