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Title: The role of neutrophils and their proteases in allergic airway disease
Author: Patel, Dhiren Ferise
ISNI:       0000 0004 6496 8926
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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An abundance of clinical data has demonstrated that a subset of asthmatic patients present with a neutrophilic infiltrate that is anticipated to be implicated in the pathology of the disease. However, this assumption is based largely on circumstantial evidence and the exact role of neutrophils in the pathophysiology of asthma has not been extensively explored. The aim of this thesis therefore was to elucidate the role of neutrophils in asthma by utilizing the house dust mite (HDM) murine model of allergic airway disease (AAD). We demonstrated that administration of HDM to different inbred mouse strains yielded very different inflammatory and airway remodelling profiles culminating variable airway hyperresponsiveness (AHR). Pertinently, whereas HDM-exposed 129/S2 mice exhibited a hyper-eosinophilic response, Balb/c mice presented with a mixed granulocytic response with a prominent neutrophilic component, which was TLR-4 independent. Specific depletion of neutrophils in HDM-exposed Balb/c mice was not protective but actually resulted in increased Th2 inflammation, with elevated ILC2s, Th2 CD4+ T cells, Th2 cytokines and serum IgE and IgG1 antibody responses. This elevated type 2 inflammation in neutrophil depleted animals was dependent on augmented Th2 cytokine production by ILC2s and a monocytosis that gave rise to enhanced antigen presentation. G-CSF was substantially elevated in neutrophil depleted mice and directly promoted the Th2 cytokine production by ILC2 and drove the monocytosis by acting on progenitors in the bone marrow. This data demonstrates that neutrophils may play a regulatory role in restricting Th2 inflammation rather than being strictly pathological. The enzyme leukotriene A4 hydrolase (LTA4H) regulates two distinct pathways that reciprocally regulate neutrophil recruitment. Classically, LTA4H functions intracellularly to generate the pro-inflammatory lipid mediator and potent neutrophil chemoattractant leukotriene B4 (LTB4). Accordingly, pharmaceutical companies have developed LTA4H inhibitors for the treatment of asthma, but they have failed to demonstrate efficacy in the clinic. Rationalizing the failure of these inhibitors, my lab have previously demonstrated a secondary extracellular anti-inflammatory role for LTA4H in degrading neutrophil chemoattractant Proline-Glycine-Proline (PGP). We have now demonstrated that mice lacking the LTB4 receptor, BLT1, showed reduced inflammation and AHR upon HDM exposure relative to wild type controls. Conversely, HDM treated lta4h-/- mice displayed an exacerbated airway resistance relative to littermate controls, despite being incapable of generating LTB4 and displaying reduced Th2 inflammation. This exacerbated airway resistance in lta4h-/- mice was attributable to a novel, neutrophil-independent, role for PGP in the context of AAD in driving pathological airway remodelling, with a pronounced epithelial hypertrophy and mucus hypersecretion apparent.
Supervisor: Snelgrove, Robert ; Lloyd, Clare Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral