The role of viral and bacterial infections in asthma exacerbations and corticosteroid resistance

Lowe, Alexander Paul 2013. The role of viral and bacterial infections in asthma exacerbations and corticosteroid resistance. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Asthma is a chronic inflammatory disease of the airways characterised by early and late asthmatic responses (EAR & LAR) to allergen, airways hyperresponsiveness (AHR) to inhaled spasmogens, airway inflammation and airway oedema. Viral infections and lipopolysaccharide (LPS) from bacteria and environmental sources contribute to exacerbations of asthma and the development of insensitivity to corticosteroids. Complete insensitivity to oral corticosteroids is rare and most patients lie on a continuum of steroid responsiveness. This thesis aimed to examine the effect of viral infection and LPS in a guinea-pig model of asthma and determine the sensitivity to inhaled and systemic corticosteroids. Sensitised guinea-pigs challenged with ovalbumin displayed EAR, LAR, AHR to histamine, airways inflammation and airway oedema. Inoculation of guinea-pigs with parainfluenza-3 virus alone induced AHR to histamine and airway inflammation. However this response was not consistent. Inhaled LPS alone induced an immediate bronchoconstriction, AHR, airway inflammation and oedema and goblet cell hyperplasia. LPS co-administered with ovalbumin exacerbated the allergen response by lengthening the EAR, prolonging the bronchoconstrictor response to histamine, increasing airway inflammation and oedema and goblet cell hyperplasia. In guinea-pigs challenged with ovalbumin alone, treatment with inhaled fluticasone propionate (FP) and inhaled and systemic dexamethasone decreased the LAR, abolished AHR, airway inflammation and oedema. Responses to LPS alone were not reduced by inhaled dexamethasone or FP but partially reduced by systemic dexamethasone. Ovalbumin and LPS combined responses were insensitive to inhaled corticosteroids, except lavage fluid protein. These responses were partially sensitive to systemic dexamethasone, with the prolonged EAR, inflammation and airway oedema all reduced. The data in this thesis suggests that LPS inhalation exacerbates ovalbumin-induced functional and inflammatory responses rendering them insensitive to inhaled corticosteroids but partially sensitive to systemic corticosteroids. Thus, the experimental combination of ovalbumin with LPS might represent a useful preclinical model of corticosteroid-insensitive airway inflammation.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords:	Asthma; Exacerbation; Corticosteroid; LPS; Virus; Model
Funders:	MRC
Date of First Compliant Deposit:	30 March 2016
Last Modified:	30 Jun 2017 03:05
URI:	https://orca.cardiff.ac.uk/id/eprint/47342

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