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Title: Mechanisms of resolution of inflammation in paediatric neutrophilic lung disease
Author: Brown, Sarah
ISNI:       0000 0004 6495 7637
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Many paediatric airway diseases are characterised by persistent neutrophilic inflammation, which can lead to damage to the airways and lung parenchyma. One possible mechanism for the persistence of neutrophilic inflammation is failure of the normal active resolution of the inflammatory process. There is limited published literature on the role of inflammatory resolution in paediatric inflammatory lung disease. It is possible that targeting inflammatory resolution mechanisms and the ability to “switch off” inflammation may provide therapeutic targets in the future for these diseases. This thesis investigates the hypotheses that failure of mechanisms terminating acute inflammation are important in the pathophysiology of infective and inflammatory lung disease; and that the differences in prognosis between childhood inflammatory lung diseases: cystic fibrosis (CF) (both established and newly diagnosed by newborn screening (CF NBS)), bronchiectasis, primary ciliary dyskinesia (PCD) and persistent bacterial bronchitis (PBB), are related to the ability to resolve inflammation in each disease. A number of mechanisms and mediators important for inflammatory resolution are described in a cross-sectional study of bronchoalveolar lavage (BAL) and endobronchial biopsies (EBB): BAL CD25+FoxP3+ T regulatory cells by flow cytometry; annexin A1 (AnxA1) and its receptor ALX by RT-PCR of BAL and RTPCR and immunofluorescent staining of EBB; the transcription factor Lung Krüppel- Like Factor by immunofluorescent staining of EBB; BAL lipid mediators by liquid chromatography – mass spectrometry and the lipid enzyme 15-lipoxygenase by immunofluorescent staining of EBB. Findings were related to underlying diagnosis, clinical status and airway inflammatory status (BAL neutrophils, CXCL8 and IL-10). The main abnormality found was in the AnxA1 axis, where BAL AnxA1 mRNA levels were lower in neutrophilic lung disease as compared to controls. However this was related to disease severity rather than the CFTR defect. The ratio of BAL CXCL8: IL- 10 was higher in CF as compared to other neutrophilic lung diseases and thus there was evidence that the ability of IL-10 to resolve CXCL8 mediated inflammation was reduced in CF. Therefore there was some evidence for the importance of inflammatory resolution mechanisms studied in the paediatric neutrophilic airway, and limited evidence to suggest that the anti-inflammatory function of IL-10 is impaired in CF.
Supervisor: Bush, Andrew ; Davies, Jane ; Lloyd, Clare Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral