In Vitro Human Airway Models for Study of Goblet Cell Hyperplasia and Mucus Production: Effects of Th2 Cytokines, Double-Stranded RNA, and Tobacco Smoke

Jennifer Bolmarcich, Sibylle Wilbert, George R. Jackson, Jr., Jonathan Oldach, Michael Bachelor, Thomas Kenney, Clifford D. Wright and Patrick J. Hayden

Goblet cell hyperplasia (GCH) within the epithelium of the conducting airways is a common feature of human respiratory diseases, including asthma and chronic obstructive pulmonary disease. GCH can be initiated or exacerbated by environmental agents, including air pollution, viral infection, and tobacco smoke. Experimental model systems for investigating causes of GCH and possible remedies are therefore of high interest. The current article utilized commercially available in vitro organotypic models of human mucociliary airway epithelium (EpiAirway™) and epithelial/stromal cocultures (EpiAirwayFT™) to characterize and compare aspects of GCH induced by Th2 cytokines, double-stranded RNA [Poly(I:C), a mimetic of viral infection], and whole cigarette smoke. Induction of GCH by interleukin (IL)-13, IL-4, Poly(I:C), and cigarette smoke was demonstrated in both the EpiAirway and EpiAirwayFT in vitro human airway models. Morphological induction of GCH was most prominent in EpiAirwayFT, while the response in EpiAirway revealed GCH overlapping with additional squamous changes and occasional appearance of epithelial voids. The results suggest that the fibroblast containing stromal component of EpiAirwayFT may play a role in modulating the outcome of epithelial exposures to these agents. Gene expression changes confirmed the induction of MUC5AC by Th2 cytokines, double-stranded RNA, and whole tobacco smoke in both EpiAirway and EpiAirwayFT. However, gene expression patterns also reveal noteworthy differences in the response to these agents. Azithromycin (AZ), a therapeutic drug that has been shown to improve clinical symptoms of pathogen and disease-associated mucus production in vivo, effectively reduced mucin protein and gene expression induction by all three agents. Taken together, the data demonstrate that organotypic in vitro human airway models are useful tools for evaluation of GCH and other clinically relevant responses to environmental agents.


Goblet cell hyperplasia (GCH), asthma, chronic obstructive pulmonary disease, COPD, EpiAirway, AIR-100-PC12, EpiAirwayFT, AFT-100-PC12, mucus production, tobacco smoke, gene expression patterns, MUC5AC, VC-1 smoking machine, LDH toxicity assay, ALOX15, BCL2, CFTR, CLCA1, FOXJ1, IRS1, IRS2, MAP2K1, MAP2K2, MUC5AC, MUC5B, PIK3R1, PRKCD, SOX2, SPDEF, SPHK1, STAT1, TFF3, TGFB2, squamous metaplasia

Materials Tested

Th2 cytokines, Poly(I:C), IL-13, IL-4, cigarette smoke, Azithromycin

Request a copy of this paper, click here.