Targeting small airway reactivity to identify novel therapies for asthma and COPD

2015

Lung diseases are highly prevalent worldwide, with asthma affecting ~10% of the population and chronic obstructive pulmonary disease (COPD) now the third leading causing of death. One of the common features of both of these diseases is small airway obstruction, caused in part by airway remodelling and increased inflammation. Current therapies aimed at reducing airway inflammation and reversing excessive airway contraction are relatively ineffective in opposing excessive contraction in small airways. In addition, respiratory viral infections in patients with asthma and COPD can also lead to exacerbations of their symptoms. Using mouse models of airway disease provides settings to assess changes in small airway reactivity and to identify potential novel therapeutic targets when current therapy is ineffective. This thesis has utilised four well-established mouse models of disease induced by exposure to the bacterial endotoxin, lipopolysaccharide (LPS), exposure to cigarette smoke (CS), infection with influenza A virus or a combination of CS exposure and influenza A virus infection. This thesis has utilised the lung slice technique as a method to assess small airway reactivity in these models of lung disease, the general hypothesis being that airway contraction would be increased and bronchodilator responsiveness would be impaired. Mice treated in vivo for four days with LPS had increased lung inflammation that was not associated with any changes in small airway reactivity to either contractile or bronchodilator agents. There was no evidence of changes in the production of anti-inflammatory cytokines or factors released from the epithelium that may be opposing inflammation-induced changes in airway contraction. Mice exposed to CS generated from 9 cigarettes a day for four days showed increases in airway inflammation (both neutrophils and macrophages). Small airway contraction to methacholine (MCh) was unaltered in lung slices from CS-exposed mice. However, the monophasi

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