Bronchial inflammation in alpha-1-antitrypsin deficiency

Hill, Adam T. (1999) Bronchial inflammation in alpha-1-antitrypsin deficiency. MD thesis, University of Glasgow.

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Chronic bronchitis was first recognised as a disabling disorder in 1808. It is often a feature of chronic obstructive pulmonary disease, and recent studies have shown that the neutrophil and in particular neutrophil elastase, released by activated neutrophils, is implicated in the pathogenesis of chronic bronchitis including the facilitation of bacterial colonisation. The degree of neutrophil influx has been shown to be associated, not only with worse lung function, but also the rate of progression of airflow obstruction. Many patients with chronic bronchitis are colonised with bacteria in the stable clinical state but it is not known how this affects upper airways inflammation, disease progression, frequency of exacerbations, or quality of life. Secretory leukoprotease inhabitor is thought to be the most critical anti-elastase in the upper airways whereas alpha-1-antitrypsin is thought to be less important, although more important at the alveolar level protecting against the development of emphysema. Patients with homozygous PiZ alpha-1-antitrypsin deficiency have decreased circulating (15-20% normal) and alveolar concentrations of alpha-1-antitrypsin which facilitate the development of early onset and rapidly progressive emphysema. About 30-40 % of these patients also have chronic bronchitis although the nature of the upper airways inflammation has not been studied. There have been few studies assessing the complex interplay of inflammatory cells and appropriate mediators in patients with chronic bronchitis. The first study in this thesis investigated patients with chronic bronchitis and a wide spectrum of neutrophil influx to assess the relationships between: neutrophil influx (as reflected by sputum myeloperoxidase concentration) and the chemoattractants interleukin 8 and leulcotriene B4; active neutrophil elastase and the chemoattractants (interleukin 8 and leukotriene B4), its own inhabitor secretory leukoprotease inhibitor, and bronchial protein leak (leakage of albumin from serum into the airways); and finally FEV1 (% predicted) and myeloperoxidase, interleukin 8 and leukotriene B4, secretory leukoprotease inhibitor, and bronchial protein leak. The results showed that both interleukin 8 and leukotriene B4 correlate with the degree of neutrophil influx and elastase activity, although the relationship with interleukin 8 and neutrophil influx appeared to be curvilinear. Elastase activity that exceeded 50nM was associated with decreased levels of secretory leukoprotease inhabitor and increased levels of bronchial protein leak. Patients with chronic bronchitis without alpha-1- antitrypsin deficiency showed a negative correlation between FEV1 (% predicted) and myeloperoxidase, interlexikin 8 and leukotriene B4, and bronchial protein leak. Although the interrelationships were often significant, they were complex, and further understanding the interaction of various mediators will require the development of specific antagonists and appropriately designed intervention studies. The second study investigated the effect of bacterial colonisation, bacterial load, and bacteria themselves on upper airways inflammation in patients with chronic bronchitis. The third study assessed upper airways inflammation in patients with chronic bronchitis with and without PiZ alpha-1-antitrypsin deficiency in the stable clinical state, to determine the importance of alpha-1-antitrypsin in the upper airways and the effects of continued smoking. The final study assessed upper airways inflammation in patients with and without alpha-1-antitrypsin deficiency during an acute exacerbation. This study revealed that there was excessive upper airways inflammation in patients with alpha-1-antitrypsin deficiency which was probably due to the low baseline alpha-1-antitrypsin levels and the reduced acute phase response

Item Type: Thesis (MD)
Qualification Level: Doctoral
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Stockley, Professor Robert
Date of Award: 1999
Depositing User: Mrs Monika Milewska-Fiertek
Unique ID: glathesis:1999-38960
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 28 Nov 2018 15:29
Last Modified: 28 Oct 2022 10:37
Thesis DOI: 10.5525/gla.thesis.38960
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