|Title:||Novel mechanisms of airway inflammation in mouse models of allergen and virus-induced asthma|
|Authors:||Ullah, MD Ashik|
house dust mite (HDM)
pneumonia virus of mice (PVM)
receptor for advanced glycation end products (RAGE)
high-mobility group box-1 (HMGB1).
|Publisher:||University of Sydney|
Woolcock Institute of Medical Research
|Abstract:||Asthma is a heterogeneous disorder encompassing distinct clinical phenotypes thought to be mediated by distinct mechanisms. The Receptor for Advanced Glycation End products (RAGE) is a pattern-recognition receptor capable of ‘sensing’ exogenous and endogenous molecules; and there is evidence that ligand-RAGE axis is activated in asthma. We investigated the role of RAGE and its ligand high-mobility group box-1 (HMGB1) in the inception and progression of allergen and virus-induced asthma using mouse models. We demonstrate that RAGE is a critical mediator of allergic airway sensitization induced by house dust mite (HDM) and cockroach (CR) allergens. Our studies suggest that RAGE is engaged secondary to the release of HMGB1 by airway epithelial cells; and that HMGB1-RAGE signalling drives type 2 immunity and airway inflammation. RAGE is also required for anti-viral immunity to pneumonia virus of mice (PVM) (equivalent to human respiratory syncytial virus). PVM infection in RAGE-deficient mice led to increased HMGB1 expression in the airways; this contributed to the development of an asthma-like pathology characterised by airway smooth muscle remodelling, airways hyperresponsiveness and the absence of granulocytic inflammation, representing a pauci-granulocytic phenotype of human asthma. In separate studies we investigated whether an anti-IL-6 receptor (IL-6R) antibody protects against allergic airway inflammation. Intriguingly, anti-IL-6R protected against CR-induced airway inflammation but exacerbated the airway inflammatory response to HDM. This differential response was related to differential activation of IL-6 signalling mechanisms in response to CR and HDM. The studies herein expose novel molecular mechanisms that may explain the development of specific phenotypes of human asthma in response to viral or allergic triggers. Selective targeting of these pathways in appropriate patient sub-groups may lead to better outcomes in asthma management.|
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|Rights and Permissions:||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
|ULLAH Md Ashik - Final thesis.pdf||Final Thesis||2.82 MB||Adobe PDF|
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