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Gene profiling of lung toxicity

Balharry, Dominique 2005. Gene profiling of lung toxicity. PhD Thesis, Cardiff University.

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Bleomycin is a potent anti-tumour compound used in the treatment of squamous cell carcinomas. An unfortunate side effect of this drug is pulmonary toxicity. The onset of this damage manifests as mild oedema and inflammation which eventually develops into pulmonary fibrosis. The ability to correctly identify patients showing early signs of lung injury could significantly reduce the morbidity associated with bleomycin treatment. As such, this study was undertaken to identify genetic markers of early oedema and inflammation. A model of mild pulmonary injury was induced by bleomycin. Conventional quantitative analysis of broncho-alveolar lavage was used to indicate the severity of the oedematous response, whilst morphological changes were identified by histology and electron microscopy. Macroarrays were used to measure the expression of multiple genes during mild, progressive and severe oedema. Following normalisation and statistical analysis, gene expression patterns were compared from saline- and bleomycin-treated rats. A variety of genes were differentially expressed during each model, with the number increasing with the severity of the oedema. A cluster and two individual genes were consistently expressed across two of the models of oedema. The magnitude of the changes in gene expression were quantified and confirmed by quantitative PCR. In summary, complete toxicological and histological characterisation of the bleomycin-induced model of pulmonary injury successfully identified specific endpoints of injury. This model proved to be ideal for studying differential gene expression in response to drug-induced pulmonary oedema. A cluster of ion channels and trafficking genes has the potential to act as a biomarker. Two specific genetic markers (Na+/CI- betaine/GABA transporter, glucocorticoid receptor), and a protein marker (cocoacrisp) have been identified for the oedema. In addition to these genes and protein being potential biomarkers of injury, they are also prospective targets for clinical treatment.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
ISBN: 9781303201325
Funders: AstraZeneca
Date of First Compliant Deposit: 30 March 2016
Last Modified: 09 Jan 2018 20:21

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