Titanium dioxide particle - induced goblet cell hyperplasia : association with mast cells and IL-13

Background: Inhalation of particles aggravates respiratory symptoms including mucus hypersecretion in patients with chronic airway disease and induces goblet cell hyperplasia (GCH) in experimental animal models. However, the underlying mechanisms remain poorly understood. Methods: To understand this, the numbers of goblet cells, Muc5ac (+) expressing epithelial cells and IL-13 expressing mast cells were measured in the trachea of sham or TiO2 particles-treated rats using periodic acid-Schiff, toluidine blue and immunohistochemical staining. RT-PCR for Muc-1, 2 and 5ac gene transcripts was done using RNA extracted from the trachea. Differential cell count and IL-13 levels were measured in bronchoalveolar lavage (BAL) fluid. In pretreatment groups, cyclophosphamide (CPA) or dexamethasone (DEX) was given before instillation of TiO2. TiO2 treatment markedly increased Muc5ac mRNA expression, and Muc5ac (+) or PAS (+) epithelial cells 48 h following treatment. Results: The concentration of IL-13 in BAL fluids was higher in TiO2 treated-rats when compared to those in sham rats (p < 0.05). Pretreatment with cyclophosphamide ( CPA) decreased the number of neutrophils and eosinophils in BAL fluid of TiO2 treated-rats ( p < 0.05), but affected neither the percentage of PAS (+) cells, nor IL-13 levels in the BAL fluids (p > 0.05). In contrast, pretreatment with dexamethasone ( DEX) diminished the percentage of PAS (+) cells and the levels of IL-13 ( p < 0.05). TiO2 treatment increased the IL-13 (+) mast cells ( p < 0.05) in the trachea, which was suppressed by DEX ( p < 0.05), but not by CPA pretreatment ( p > 0.05). In addition there were significant correlations of IL-13 (+) rate of mast cells in the trachea with IL-13 concentration in BAL fluid (p < 0.01) and with the percentage of Muc5ac (+) cells in the sham and TiO2 treated rats ( p < 0.05). Conclusion: In conclusion, TiO2 instillation induces GCH and Muc5ac expression, and this process may be associated with increased production of IL-13 by mast cells.