Abstract
RationaleEpithelial remodelling in asthma is characterised by goblet cell hyperplasia and mucus hypersecretion for which no therapies exist. Differentiated bronchial air-liquid interface cultures from asthmatic children display high goblet cell numbers. Epidermal growth factor and its receptor have been implicated in goblet cell hyperplasia.ObjectivesWe hypothesised that EGF removal or tyrphostin AG1478 treatment of differentiating air-liquid interface cultures from asthmatic children would result in a reduction of epithelial goblet cells and mucus secretion.MethodsIn Aim 1 primary bronchial epithelial cells from non-asthmatic (n = 5) and asthmatic (n = 5) children were differentiated under EGF-positive (10ng/ml EGF) and EGF-negative culture conditions for 28 days. In Aim 2, cultures from a further group of asthmatic children (n = 5) were grown under tyrphostin AG1478, a tyrosine kinase inhibitor, conditions. All cultures were analysed for epithelial resistance, markers of differentiation using immunocytochemistry, ELISA for MUC5AC mucin secretion and qPCR for MUC5AC mRNA.ResultsIn cultures from asthmatic children the goblet cell number was reduced in the EGF negative group (p = 0.01). Tyrphostin AG1478 treatment of cultures from asthmatic children had significant reductions in goblet cells at 0.2μg/ml (p = 0.03) and 2μg/ml (p = 0.003) as well as mucus secretion at 2μg/ml (p = 0.04).ConclusionsWe have shown in this preliminary study that through EGF removal and tyrphostin AG1478 treatment the goblet cell number and mucus hypersecretion in differentiating air-liquid interface cultures from asthmatic children is significantly reduced. This further highlights the epidermal growth factor receptor as a potential therapeutic target to inhibit goblet cell hyperplasia and mucus hypersecretion in asthma.
Highlights
Asthma is a disease that normally begins during childhood [1, 2] progressing into adulthood with airways remodelling including goblet cell hyperplasia due to chronic inflammation
We have shown in this preliminary study that through epidermal growth factor (EGF) removal and tyrphostin AG1478 treatment the goblet cell number and mucus hypersecretion in differentiating air-liquid interface cultures from asthmatic children is significantly reduced
We have previously shown that the Th2 cytokine interleukin 13 (IL-13) caused goblet cell hyperplasia, decreased ciliated cell number and increased mucus secretion in differentiating cultures of healthy epithelial cells while IL-13 stimulation of differentiating air-liquid interface (ALI) cultures from asthmatic children showed increased goblet cell number [7]
Summary
Asthma is a disease that normally begins during childhood [1, 2] progressing into adulthood with airways remodelling including goblet cell hyperplasia due to chronic inflammation. Under unstimulated conditions where an inherent goblet cell hyperplasia existed we detected no IL-13 mRNA or protein. We deduced that while IL-13 can induce an asthmatic phenotype, it was unlikely to be the cause of the inherent goblet cell hyperplasia seen in unstimulated ALI cultures from asthmatic children [7]. This lead us to consider epidermal growth factor (EGF) and its receptor (EGFR) which have been shown to induce MUC5AC via ERK pathway activation as ERK inhibition effectively reduces MUC5AC mRNA production and promoter activity [8]. There have been attempts to target mucus hypersecretion using mucoactive drugs these have provided minimal benefit [9]
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