Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.769269
Title: Nanoparticles, sensory irritation and the lung : environmental influences on biological processes
Author: Robinson, Ryan Karis
ISNI:       0000 0004 7656 9607
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
Availability of Full Text:
Access from EThOS:
Access from Institution:
Abstract:
Diesel exhaust particles (DEP) have been shown in epidemiological studies to be associated with respiratory symptoms. The cellular mechanisms driving these effects continue to be investigated. However, one aspect of lung physiology that has not been studied is the potential for DEP to activate transient receptor potential (TRP) ion channels expressed on airway sensory nerves. The aim of this thesis was to determine whether DEP could activate airway sensory nerves and the underlying mechanisms involved. In the anesthetised guinea pig, it was established that DEP induced action potential firing in chemosensitive C-fibre airway afferents in vivo, but had no effect on mechanosensitive A-δ fibres. DEP was also shown to activate airway sensory nerves in vitro. Physicochemical characterisation of DEP indicated that it was mainly composed of inorganic carbon with the remainder organic hydrocarbons and trace impurities. It was demonstrated that the organic components of DEP (DEP-OE) were capable of activating the vagus nerve, while the carbon core had no effect. With the use of pharmacological tools and tissue from genetically modified mice, activation of sensory nerves by DEP-OE in vitro was found to be mediated by TRPA1. DEP-OE induced action potential firing was also inhibited by TRPA1 antagonism in vivo. Application of antioxidants abolished responses to DEP-OE, demonstrating a role for oxidative stress which is a known activator of TRPA1. Polycyclic aromatic hydrocarbons (PAHs) present in DEP-OE were found to activate sensory nerves and this activation was also inhibited by TRPA1 antagonism. PAHs responses were inhibited by aryl hydrocarbon receptor (AhR) antagonists. Responses to DEP-OE were also inhibited by AhR antagonists, and were reduced in AhR-/- mice. It was hypothesised that AhR induced oxidative stress through an association with the mitochondria, and the application of a specific mitochondrial superoxide scavenger inhibited responses to DEP-OE. A novel neuronal mechanism by which DEP exposure can activate airway sensory nerves has been identified. Potential therapeutic targets may be developed to protect susceptible individuals from the adverse health effects of air pollution. In a wider context, the results of this thesis could also be used as additional evidence for the need to reduce the levels of diesel emissions in the urban environment.
Supervisor: Belvisi, Maria ; Tetley, Terry ; Porter, Alexandra Sponsor: Asthma UK ; Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.769269  DOI:
Share: