Examination of viral and bacterial exacerbations of airways inflammation and function

Doctoral thesis English OPEN
Davies, Ceri Mark
  • Subject: Q1

Chronic obstructive pulmonary disease (COPD) is an umbrella term that encompasses\ud chronic bronchitis, emphysema and airway obstruction. COPD patients are also prone to\ud acute exacerbations (AECOPD) caused primarily by viral and bacterial infection, which\ud leads to an increase in inflammation, a worsening of symptoms and can lead to death. There\ud is an unmet clinical to better understand and treat AECOPD as well as COPD in general, but\ud this is hindered by unreliable animal models of COPD and AECOPD. The aim of this thesis\ud was to establish an animal model of COPD that could be exacerbated by an infectious agent.\ud Firstly an LPS model of COPD was established in the guinea pig, which resulted in a\ud macrophage and neutrophil inflammatory profile, emphysematous changes, a decrease in\ud lung function and partial steroid insensitivity that could be partially reversed with low dose\ud theophylline. Human parainfluenza 3 virus failed to cause any infection in the guinea pig, so\ud a model of AECOPD could not be established in this model.\ud A chronic cigarette smoke model in the mouse was established, which again demonstrated a\ud similar phenotype to COPD. This model was able to be exacerbated by the bacteria nontypeable\ud Haemophilus influenza (NTHi) with increases in neutrophils and the neutrophil\ud chemoattractant CXCL1. However, it was also observed that while NTHi could exacerbate\ud the model, responses to NTHi in cigarette smoke challenged mice compared to sham\ud challenged animals were impaired, with significant decreases in CXCL8, TNF-α, IFN-γ and\ud IL-10. This impairment was also observed in monocyte derived macrophages (MDMs)\ud challenged with cigarette smoke extract (CSE) with significant impairment of Il-1β, while\ud chronic LPS challenge also impaired Il-6 and phagocytosis.\ud The data in this thesis highlights a possible increase in steroid responses by low dose\ud theophylline in an LPS model in the guinea pig. It has also demonstrated chronic cigarette\ud smoke exposure in the mouse can be exacerbated by NTHi, however the inflammatory\ud response is impaired compared to sham challenged animals suggesting that cigarette smoke\ud impairs the innate immune response. MDMs also demonstrated an impaired response to\ud NTHi after CSE or LPS challenge.\ud iii
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