A bench to bedside investigation into defective innate immunity in chronic obstructive pulmonary disease
File(s)
Author(s)
Batista, Craig
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2017-09
Date Awarded
2018-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Donnelly, Louise
Barnes, Peter
Sponsor
National Institute for Health Research (Great Britain)
Cempra Pharmaceuticals (Firm)
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)