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Toxicological assessment of the pulmonary response to air pollution particles.

Wise, Helen. 2004. Toxicological assessment of the pulmonary response to air pollution particles. PhD Thesis, Cardiff University.

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There is strong epidemiological evidence of association between PMi0 (particulate matter with an aerodynamic diameter less than or equal to 10 microns) and adverse health outcomes including death and increased hospital admissions for cardio-pulmonary conditions. Ambient PMi0 surrogates such as diesel exhaust particles (DEP), a common component of UK PMi0, have been shown to induce lung inflammation in both humans and rodents. To date, few studies have reported on the toxicological response of UK PM 0 in experimental animals. This thesis summarises the characterisation of the pulmonary toxicity of Cardiff urban PM10. Firstly, the pulmonary toxicological responses in male Sprague Dawley rats following the intratracheal instillation of Cardiff urban PM 0 were examined. A mild, but significant, change in lung permeability was observed in the lung post instillation of a high (10 mg) dose of the whole PMi0 as adjudged by increases in lung to body weight ratio and total acellular lavage protein. Such effects were less marked following instillation of a water-soluble fraction (80% of the total mass) but histological examination showed that lung capillaries were swollen in size with this treatment. Secondly, expression profiling of PM exposed lung tissue identified distinct genes differentially expressed as a consequence of exposure to a high dose (10 mg) of whole PM and equivalent dose of water soluble component of PM. Such changes were linked to different histopathological events within the lung. In conclusion, conventional toxicological, histological and toxicogenomic studies have indicated that Cardiff PM10 exhibits low bioreactivity in the form of mild permeability changes. In vitro toxicological assessment of the bio reactivity of the PM sample using primary cultures of epithelial type II and alveolar macrophage cells were used to identify the relative contribution of the different fractions (whole, washed "durable" fraction and water soluble component) to the overall PM toxicity. Correlations with total metal content and particle size were identified in the different cell types. Cellular analysis using advanced fluorescence labelling and microscopy identified the ability of the PM to induce subtle changes in cell and nuclear morphology that may result in increased cell death and apoptosis even at low particulate doses. Expression profiling of the PM exposed cells proved difficult and realised limited information regarding the cellular responses to the toxicant. This approach failed to identify the same gene changes reported in the lung tissue profiling, illustrating the importance of the different cell types within the lung to orchestrate a pulmonary response. In conclusion, the use of toxicogenomics and gene expression arrays in toxicological is still relatively novel approach to the assessment of lung injury. The study addresses initial problems and offers some possible solutions regarding the use of macro arrays and expression profiling in toxicology research. Expression arrays offer considerable scope as a research tool and in future will provide a powerful insight into gene changes on a global scale.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
ISBN: 9781303200182
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 Oct 2017 15:29

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