Mechanisms of resolution of inflammation in paediatric neutrophilic lung disease
File(s)
Author(s)
Brown, Sarah
Type
Thesis or dissertation
Abstract
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.
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.
Version
Open Access
Date Issued
2015-02
Date Awarded
2016-02
Advisor
Bush, Andrew
Davies, Jane
Lloyd, Clare
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Medicine (Research) MD (Res)