[Truncated abstract] Lung transplantation remains the only viable treatment option for many end stage pulmonary diseases and with improvements in surgical techniques and immunosuppression deaths in the first post-operative year has been reduced to less than 10%. However, longer term outcomes are compromised largely by the development of bronchiolitis obliterans syndrome (BOS). BOS is characterized clinically by progressive airflow obstruction leading to respiratory failure, and histologically by fibroproliferative obliteration of the small airways - obliterative bronchiolitis. Since there is no effective treatment, BOS is the cause of 80% of all post transplant deaths after the first year. There are very few viable treatment options, since immunosuppression strategies have not been able to prevent or reverse BOS significantly. Recent studies have shown that macrolides such as azithromycin may be able to prevent BOS in some cases. However, the mechanism of action of these macrolides is still unclear, and if the treatment is unsuccessful the only other option is re-transplantation. The pathogenesis of BOS remains poorly understood but recent evidence suggests that fibrotic obliteration occurs as the result of transformation of epithelial cells into a mesenchymal phenotype. This process is called epithelial-mesenchymal transition (EMT). The process is characterized by a decrease in the expression of mesenchymal markers, a subsequent increase in the expression of epithelial markers, and an increase in the activity of matrixmetalloproteinases 2&9. Even though EMT can be initiated by different mechanisms, the most common stimulator appears to be an excess of the cytokine transforming growth factor (TGF) β1.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2011|