Veterinary Science - Theses
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ItemEpithelial remodelling in a sheep model of asthma( 2013)The airway epithelium is the barrier to inhaled allergens and other agents and thus plays a central role in the restriction of, and response to, such insults. In asthma, ineffective barrier function and aberrant epithelial signalling are believed to be important in both the development and exacerbation of asthma. A review of the literature suggests that rodent models of asthma might not accurately represent the healthy or consequently the diseased airway epithelium of humans. Furthermore, little is known about small airway epithelial remodelling or the long-term effects of allergen exposure in the absence of continued antigenic stimulation. This thesis sought to firstly characterise epithelial remodelling following house dust mite (HDM) allergen challenge in a sheep model of experimental asthma (Chapters 3 and 4). In this model, chronic allergen challenge resulted in the induction of asthmatic features including goblet cell hyperplasia, epithelial hypertrophy, increased EGFR expression and allergen-induced proliferation of airway epithelial cells. Also provided is the first evidence for allergen induced goblet cell degranulation in a non-rodent system, and for degranulation induced via a relevant human allergen (HDM). The long-term effects of allergen exposure on the epithelium were also examined. Epithelial remodelling induced through chronic exposure to HDM remained for three months following the cessation of direct allergen challenge (Chapter 4). Goblet cell hyperplasia, epithelial hypertrophy and epithelial growth factor receptor (EGFR) expression remained in the absence of continued direct allergen challenge, indicative that the epithelium does not require continued allergen exposure to retain an asthmatic phenotype. Microarray analysis of epithelial brushing biopsies (Chapter 5), again demonstrated allergen driven epithelial cell proliferation and a general asthmatic phenotype including the down regulation of cellular tight junction mRNA. Subsequent qPCR validation demonstrated the transcriptional downregulation of the Bone morphogenetic protein (BMP) inhibitor noggin and the tight junction gene occludin in the more severe asthmatic sheep but not in those animals with a less severe phenotype. The downregulation of occludin mRNA was evident both prior to and throughout the establishment of chronic epithelial remodelling. In conclusion this thesis has demonstrated the induction of common asthmatic epithelial changes through chronic allergen challenge in a large animal model, and the retention of this asthmatic phenotype in the absence of continued stimulation. The persistence of epithelial remodelling is an interesting finding given its role as the first line of defence to the external environment. The knowledge gained in this thesis may have useful implications for future therapeutic strategies.