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Title: Extracellular matrix proteolysis by bronchoalveolar leukocytes in experimental pneumoconiosis
Author: Brown, Geraldine Marie
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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Neutral proteinases, released by inflammatory leukocytes, have been implicated in the pathogenesis of pneumoconiosis but there has been no systematic study of the proteolytic acitivty of leukocytes from dust-exposed lung. The aim of the present study was, therefore, to assess the bronchoalveolar leukocyte profile and proteolytic activity of the leukocytes in a rat model of pneumoconiosis. An assay, based on the breakdown of [125I] fibronectin, that would measure the overall proteolytic activity of the bronchoalveolar leukocytes and indicate their potential to damage the connective tissue of the alveolar septum was developed and validated. Increased proteolytic activity was found in the inflammatory bronchoalveolar leukocyte populations and so the relative role of macrophages and neutrophils was assessed by separation into distinct populations; both inflammatory macrophages and neutrophils had increased proteolytic activity. The important features governing the inflammogenicity of particles were addressed by measuring the inflammation-generating properties of a variety of fibrogenic and non-fibrogenic particles in rats exposed by intratracheal instillation or inhalation. The number of leukocytes recruited to the alveolar region was measured by bronchoalveolar lavage. Only fibrogenic mineral dusts had the ability to produce a sustained alveolitis in which the proteolytic activity of the bronchoalveolar leukocytes remained elevated. The pathogenicity of fibrogenic particles is likely, therefore, to be related to their ability to evoke and sustain an increased lung proteinase burden. The sustained alveolitis with fibrogenic particles was not related to lack of clearance of dust from the lung. Both quartz and coalmine dust elicited persistent alveolitis, but titanium dioxide, which is no more readily cleared than silica or coalmine dust, failed to sustain the inflammation. Properties of the particle surface, at least in the case of quartz, appear to play a part in their inflammogenicity. Altering the surface of quartz particles by coating them with aluminium lactate reduced their ability to recruit inflammatory leukocytes but did not alter the proteolytic activity of the leukocytes. The tissue response to the aluminium-coated quartz particles was also less than that elicited by native quartz with fewer and less-severe lesions. The foregoing serve to substantiate the role of inflammatory leukocytes in the pathogenesis of pneumoconiosis. Only when there is a sustained alveolitis with an overall increased proteinase burden, does pathological change occur in the lung. Reducing the magnitude and/or the duration of the alveolitis markedly suppresses the development of the tissue lesions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available