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Title: The role of innate immune system receptors in smoking related disease
Author: Parzych, Katarzyna
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Cigarette smoke induces inflammation, in part, by activation of Toll like receptor (TLR) 2 and TLR4. TLRs are present on most cells and recognize pathogen associated molecular patterns (PAMPs) and non-pathogenic molecules, known as danger associated molecular patterns (DAMPs). Activation of TLRs results in the propagation of a signalling pathway leading to the de novo synthesis of pro-inflammatory mediators that include CXCL8 and IL-1β. TLRs initiate inflammation and are involved in tissue repair processes in a number of diseases such as chronic obstructive pulmonary disease (COPD) and cancer. Therefore, it is the aim of this thesis to explore the contribution of TLRs in inflammation and cellular proliferation, as these processes are integral to the pathology in inflammatory lung disease and cancer. Activation of IL-1β is a two-step process. The first step synthesises pro-IL-1β and can be activated by TLR ligands. The second induces inflammasome complex assembly and results in the cleavage of pro-IL-1β to mature IL-1β by caspase-1. IL-1β is implicated in the inflammation caused by bacteria during exacerbations in lung disease. Interestingly, we found a difference in the activation and release of IL-1β from monocytes activated with the TLR2 ligand, Pam3CSK4 and the TLR4 ligand, LPS. The difference was seen at the level of inflammasome assembly, where, unlike TLR4, TLR2-induced IL-1β release was reliant on the hemichannel protein, pannexin-1. We have previously found that cigarette smoke causes sensitisation of the blood of smokers to bacterial and viral PAMPs. Cigarette smoke is the major contributing factor in COPD and it is known that bacterial and viral induced exacerbations play a major role in the deterioration of lung function in these patients. COPD patients are also more prone to lung infections than their healthy age-matched equivalents. We therefore hypothesised that blood from COPD patients is more sensitive to challenge with bacterial and viral PAMPs than blood from age-matched controls. COPD patient’s blood had an increased sensitivity to challenge with TLR2/1 and TLR3 ligands with respect to IL-1β release. Regarding CXCL8 release in this system, a greater response to stimulation with TLR2/1, TLR3, TLR4 agonists and IL-1β was observed in blood from COPD patients. There was a negative correlation between CXCL8 levels and COPD GOLD staging in response to TLR4 agonism. TLR2 has been implicated in the proliferation of cancer cells. There is an emerging interest in the link between chronic inflammation and cancer. It is well documented that COPD patients have an increased risk of developing lung cancer, which has poor prognosis. Our aim was to investigate whether TLRs are a novel drug target for inhibiting the proliferation of lung cancer cells. TLR2, 3, 4 and 7 agonists had no effect on lung cancer cell proliferation; however, activation of TLR8 induced apoptosis in these cells. In conclusion, my thesis shows that TLRs are important receptors involved in the initiation of inflammation and inhibition of cellular proliferation. We show, for the first time, that TLR4-induced CXCL8 release in COPD patients may be a good biomarker of disease severity, and that TLR8 offers a good prospect as an adjuvant in the treatment of lung cancer.
Supervisor: Mitchell, Jane ; Paul-Clark, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available