A bench to bedside investigation into defective innate immunity in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is characterised by inflammation that is unresponsive to corticosteroids. Innate immunity appears to be defective and may contribute to this inflammatory pathophysiology. This is exemplified by upregulated inflammatory mediators and ineffective bacterial phagocytosis by alveolar macrophages (AM). This thesis compares phagocytosis by macrophages from non-smokers, smokers and COPD patients. The mechanisms underpinning defective bacterial phagocytosis are investigated and the potential anti-inflammatory effects of novel immunomodulatory compounds explored. Correlations were observed between the phagocytosis of paired AM and monocyte-derived macrophages (MDM) from COPD patients and controls. MDM were therefore adopted as a model. Defective bacterial phagocytosis was confirmed in MDM, relative to non-smoking controls and when using H. influenzae and S. pneumoniae. The magnitude of this defect did not correlate with FEV1, symptom-burden or exacerbation frequency, but defective bacterial phagocytosis was associated with less stable microtubule polymers. Solithromycin is a novel macrolide antibiotic with immunomodulatory properties and a low potential for microbial resistance. Although it was unable to augment defective bacterial phagocytosis, it did inhibit LPS-stimulated TNF-α release by MDM. This property was shared by several analogues, some of which were inactive against common respiratory pathogens (i.e. pure immunomodulators). The anti-inflammatory effects of oral solithromycin were therefore studied in vivo, during a randomised, placebo-controlled, clinical trial. To aid this investigation, a novel sampling technique was first developed, using synthetic absorptive matrix to sample the nasal epithelial lining fluid as a less invasive surrogate measure of bronchial inflammation. However, treatment with 400 mg of solithromycin for 28 days proved hepatotoxic in COPD and the trial was terminated early. Bacterial phagocytosis is defective in COPD. It might arise from unstable microtubule polymers and permit colonisation with pathogenic bacteria. It therefore represents a novel antiinflammatory target. Although solithromycin is immunomodulatory, its therapeutic application is limited in COPD by hepatotoxicity.