Investigations on the Role of the Renin-Angiotensin System in Asthma

Ramsay, Scott Gordon (1999) Investigations on the Role of the Renin-Angiotensin System in Asthma. MD thesis, University of Glasgow.

Abstract

The renin-angiotensin system is activated in acute severe asthma although the mechanism for is unclear. Angiotensin II is a weak bronchoconstrictor, potentiates the effects of other bronchoconstrictors and can be formed by inflammatory proteases. In vitro, angiotensin II is a growth promoter for human airway smooth muscle cells. The insertion/deletion polymorphism of the ACE gene accounts for variation in ACE activity and the deletion allele may be more frequent in asthmatics. In view of these facts, further clarification of the role of the renin-angiotensin system in asthma is required. Aims This thesis examines the factors causing activation of the renin-angiotensin system in acute severe asthma, the role of the ACE gene polymorphism, the putative effects of angiotensin II on the action of histamine in the human airway both in vitro and in vivo, the effects of angiotensin II on rat airway smooth muscle cell growth in vivo and seeks evidence for the existence of a local renin-angiotensin system in the human lung. 1. Mechanism of Activation of the Renin-Angiotensin System in Asthma Clinical data were obtained from 40 acute asthmatic hospital admissions and correlated with plasma levels of renin and angiotensin II. The genotype for the ACE gene polymorphism was determined in this group, a group of 20 non-asthmatic acute medical hospital admissions and 78 healthy volunteers to allow comparison of allele frequencies and correlation with both ACE activity and angiotensin II levels. Plasma renin and angiotensin II were elevated in some, but not all of the acute asthmatics and no correlation was found with any of the parameters measured. The DD homozygote for the ACE gene polymorphism had the highest ACE activity in all groups measured. There was a non-significant trend towards an increased frequency of the deletion allele in asthmatics compared with normal controls. An unexpected finding was the increased ACE activity for the DD and ID genotypes found in acute hospital admissions compared with healthy controls. The clinical significance of this is uncertain. 2. Effect of Angiotensin II on Histamine-Induced Bronchoconstriction The effect of angiotensin II on histamine-induced contraction of human bronchial rings in vitro was examined by constructing concentration-response curves to histamine (10-9M - 3x10-4M) in the presence and absence of sub-threshold doses of angiotensin II (10-7M - 10-6M). This was also studied in vivo in 8 asthmatic volunteers who had histamine bronchial provocation testing in a double-blinded fashion in the presence of infusions of placebo (5% dextrose) and angiotensin II (1 and 2 ng/kg/min). Angiotensin II in subthreshold doses for contraction of airway smooth muscle had no effect on histamine-induced bronchoconstriction in the human airway neither in vitro nor in vivo. 3. Effect of Angiotensin II on Remodelling of Rat Airway & Vasculature The effect of endogenous activation of the renin-angiotensin system by dietary sodium restriction and subcutaneous infusion of angiotensin II on the rat airways was compared to the mesenteric vasculature. DNA synthesis was measured by infusing the thymidine analogue bromo-2'-deoxyuridine subcutaneously then revealing those cells undergoing DNA synthesis using immunocytochemistry. Changes in the volume of the airway tissues were measured morphometrically. Endogenous activation of the renin-angiotensin system in rats known to increase arterial medial DNA synthesis results in increased renin mRNA expression in the renal juxta-glomerular cells with increased plasma aldosterone and plasma renin activity and manor insignificant variations in blood pressure. However, no change was seen m DNA synthesis or morphometry of the airways. Similarly, infusion of angiotensin II for two weeks in rats causes a rise in blood pressure and suppresses renal juxta-glomerular renin mRNA expression with a nonsignificant suppression of plasma renin activity. DNA synthesis increased in the mesenteric arterial media and there was a non-significant tendency towards the artery wall being thicker. No difference was found in DNA synthesis or morphometry of the airways. 4. Evidence for a Local Renin-Angiotensin System in the Human Lung Samples of normal human lung were obtained from thoracotomy specimens and were examined by immunocytochemistry for renin and ACE, and by in situ hybridisation and Northern blotting for renin mRNA, angiotensinogen mRNA, ACE mRNA and AT1 receptor mRNA. In situ angiotensin II receptor localisation and autoradiography were also performed. In human lung, ACE was identified in vascular endothelium however, no other components of the renin-angiotensin system could be found. In control rat lung tissue, angiotensin II receptors appeared to be present. Conclusion The renin-angiotensin system is activated in some acute asthmatics but the mechanism for this remains unclear.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Ian McKay
• Keywords: Medicine, Immunology
• Date of Award: 1999
• Depositing User: Enlighten Team
• Unique ID: glathesis:1999-75422
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 20:09
• Last Modified: 19 Nov 2019 20:09
• URI: https://theses.gla.ac.uk/id/eprint/75422