Airway wall remodelling contributes to decreased lung function in asthma. Key features of the remodelling process are thickening of the reticular basement membrane, differentiation of fibroblast-like cells with contractile properties termed myofibroblasts and sub-epithelial deposition of extracellular matrix.The pro-fibrogenic cytokine transforming growth factor-β2 (TGF-β2) is purported to drive remodelling responses. TGF-β2 may be upregulated in asthmatic epithelium, and is secreted by bronchial epithelial cells following injury. In this study significant increases in reticular basement membrane thickening and myofibroblast differentiation were identified by histology and immunohistochemistry of mild asthmatic and healthy human bronchial biopsy tissue, although no significant differences in TGF-β2 expression were identified. It was hypothesised that the proteolytic action of house dust mite (HDM) allergens would lead to increased activation of latent TGF-β2 secreted by bronchial epithelial cells. A transformed cell line, 16HBE14o-, did not show increased activation or expression following HDM extract challenge, however TGF-β2 activation and expression was increased following exposure of primary human bronchial epithelial cells to a HDM extract. Myofibroblast differentiation and matrix deposition by healthy and mild asthmatic- derived primary bronchial fibroblasts were assessed by alpha-smooth muscle actin expression and soluble collagen production, following challenge with exogenous TGF-β2. Results presented here show asthmatic bronchial fibroblasts are more sensitive to the myofibroblast priming effects of TGF-β2. Bronchial epithelial cell conditioned media challenge of healthy fibroblasts led to greater increases in matrix deposition and myofibroblast differentiation than was attributable to TGF-β2, with greatest increases seen following asthmatic epithelial cell conditioned media exposure. Responses were greater than suggested by the epithelial TGF-β2 levels, so it is suggested that additional soluble mediators play a part in airway wall remodelling responses. Further work is required to identify the soluble mediators secreted by bronchial epithelial cells that control the responses of the underlying fibroblasts.
|Date of Award||1 Aug 2011|
- The University of Manchester
|Supervisor||Robin Gore (Supervisor) & Sarah Herrick (Supervisor)|