Endothelin-1 and the use of induced sputum to investigate its role in airway diseases

Chalmers, George W (1999) Endothelin-1 and the use of induced sputum to investigate its role in airway diseases. MD thesis, University of Glasgow.

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Abstract

Endothelin (ET)-1 is a 21-amino acid peptide which has been the subject of intense interest since its discovery in 1988. It has a number of properties which may be important in physiology and pathophysiology, including potential relevance to airway diseases. A putative role for ET-1 in asthma has been proposed, and we sought to examine this further, as well as to extend our investigations to other respiratory diseases, including chronic obstructive pulmonary disease and cystic fibrosis. The technique of sputum induction has been developed recently as a non-invasive method of obtaining airway secretions for analysis, and we have applied this to the investigation of the role of ET-1 in diseases involving the airway. We have demonstrated for the first time that ET-1 is a highly potent bronchoconstrictor with a prolonged duration of action when administered by aerosol in asthma, and that asthmatics exhibit bronchial hyperreactivity to ET-1 compared with non-asthmatic subjects, but we found no evidence of an acute inflammatory airway response at 30 minutes or 4 hours following ET-l-induced bronchoconstriction in asthma, assessed by analysis of cell counts and soluble mediators in induced sputum. The bronchoconstrictor activity of ET-1 was not potentiated by an infusion of angiotensin II in stable asthmatics, despite animal evidence of potentiation, although the possibility of such interaction remains in acute severe asthma, where plasma angiotensin II levels are elevated. We did not find increased levels of ET-1 in induced sputum in mild asthmatics compared with non-asthmatic subjects, nor was there a fall in sputum ET-1 comparing samples obtained during acute severe asthma with those obtained in convalescence, although sputum and saliva levels of ET-1 are greater than plasma ET-1, suggesting local production within the respiratory tract. Examination of sputum ET-1 following allergen challenge in asthma showed a trend towards an increase in sputum ET-1 after allergen challenge, with a relationship between the increase in sputum ET-1 and the extent of sputum eosinophilia, suggesting a relationship between asthmatic airway inflammation and ET- 1 release. Sputum ET-1 is increased in smokers without lung disease, and in subjects with chronic obstructive pulmonary disease (COPD), with a trend towards a fall in sputum ET-1 comparing acute exacerbation with convalescence. Finally, we have demonstrated a marked increase in sputum ET-1 in patients with cystic fibrosis compared with healthy subjects. We conclude from this series of studies that there is continuing evidence for a role for ET-1 in a number of diseases affecting the airway, and speculate that drugs which oppose the action of ET-1 may have a role in the treatment of these conditions.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Neil Thomson
Keywords: Immunology
Date of Award: 1999
Depositing User: Enlighten Team
Unique ID: glathesis:1999-72003
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 May 2019 13:26
Last Modified: 17 May 2019 13:26
URI: http://theses.gla.ac.uk/id/eprint/72003

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